bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Cancer Prevention with Resistant Starch in Lynch Syndrome Patients in the CAPP2-Randomized Placebo Controlled Trial: Planned 10-Year Follow-up
Authors: Mathers John C. , Elliott Faye , Macrae Finlay , Mecklin Jukka-Pekka , Möslein Gabriela , McRonald Fiona E. , Bertario Lucio , Evans D. Gareth , Gerdes Anne-Marie , Ho Judy W.C. , Lindblom Annika , Morrison Patrick J. , Rashbass Jem , Ramesar Raj S. , Seppälä Toni T. , Thomas Huw J.W. , Sheth Harsh J. , Pylvänäinen Kirsi , Reed Lynn , Borthwick Gillian M. , Bishop D. Timothy , Burn John
Published: April 2023

Abstract
The CAPP2 trial investigated the long-term effects of aspirin and resistant starch on cancer incidence in patients with Lynch syndrome (LS). Participants with LS were randomized double-blind to 30 g resistant starch (RS) daily or placebo for up to 4 years. We present long-term cancer outcomes based on the planned 10-year follow-up from recruitment, supplemented by National Cancer Registry data to 20 years in England, Wales, and Finland. Overall, 463 participants received RS and 455 participants received placebo. After up to 20 years follow-up, there was no difference in colorectal cancer incidence (n = 52 diagnosed with colorectal cancer among those randomized to RS against n = 53 on placebo) but fewer participants had non-colorectal LS cancers in those randomized to RS (n = 27) compared with placebo (n = 48); intention-to-treat (ITT) analysis [HR, 0.54; 95% confidence interval (CI), 0.33–0.86; P = 0.010]. In ITT analysis, allowing for multiple primary cancer diagnoses among participants by calculating incidence rate ratios (IRR) confirmed the protective effect of RS against non–colorectal cancer LS cancers (IRR, 0.52; 95% CI, 0.32–0.84; P = 0.0075). These effects are particularly pronounced for cancers of the upper GI tract; 5 diagnoses in those on RS versus 21 diagnoses on placebo. The reduction in non–colorectal cancer LS cancers was detectable in the first 10 years and continued in the next decade. For colorectal cancer, ITT analysis showed no effect of RS on colorectal cancer risk (HR, 0.92; 95% CI, 0.62–1.34; P = 0.63). There was no interaction between aspirin and RS treatments. In conclusion, 30 g daily RS appears to have a substantial protective effect against non–colorectal cancer cancers for patients with LS.
Prevention Relevance:
Regular bowel screening and aspirin reduce colorectal cancer among patients with LS but extracolonic cancers are difficult to detect and manage. This study suggests that RS reduces morbidity associated with extracolonic cancers.

See related Spotlight, p. 557
Data from Association Between Diet and Fusobacterium nucleatum in the Feces of Healthy Adults: A Hospital-based Cross-sectional Study
Authors: Narii Nobuhiro , Zha Ling , Sobue Tomotaka , Kitamura Tetsuhisa , Shiba Satoshi , Mizutani Sayaka , Yamada Takuji , Yachida Shinichi
Published: April 2023

Abstract
Fusobacterium nucleatum is involved in the development and progression of colorectal cancer. Although the gut microbiota is influenced by diet, studies on the association between diet and F. nucleatum are limited. We aimed to evaluate the association between various dietary factors and fecal F. nucleatum in healthy adults without a history of colorectal cancer or precancerous lesions. This was a cross-sectional study. Subjects who underwent total colonoscopy at the National Cancer Center Hospital (Tokyo, Japan) were included. Healthy subjects (n = 212) were divided into two groups according to the presence or absence of F. nucleatum in their feces which was calculated from data of whole-genome shotgun sequencing, with the group with F. nucleatum serving as cases and the group without F. nucleatum serving as controls. Multivariable logistic regression analysis adjusted potential confounders was conducted to estimate the associations between dietary intake and nutrients estimated by a validated food frequency questionnaire and the presence of F. nucleatum in the feces. There was a significant inverse association between dairy products and the presence of fecal F. nucleatum [high vs. low; OR, 0.41; 95% confidence interval, 0.17–0.95; Ptrend, 0.039]. These results may have important implications for colorectal cancer prevention through nutritional intervention.
Prevention Relevance:
F. nucleatum is well known as a colorectal cancer–associated bacterium. Dietary habits alter the composition and function of the intestinal microbiota. A high intake of dairy products in healthy adults may reduce F. nucleatum and prevent colorectal cancer.
Data from Benign Breast Disease, NSAIDs, and Postmenopausal Breast Cancer Risk in the CPS-II Cohort
Authors: Sherman Mark E. , Vierkant Robert A. , Masters Matthew , Radisky Derek C. , Winham Stacey J. , Degnim Amy C. , Vachon Celine M. , Patel Alpa V. , Teras Lauren R.
Published: April 2023

Abstract
Nonsteroidal anti-inflammatory agents (NSAID) are associated with modest inconsistent reductions in breast cancer risk in population-based cohorts, whereas two focused studies of patients with benign breast disease (BBD) have found lower risk with NSAID use. Given that BBD includes fibroinflammatory lesions linked to elevated breast cancer risk, we assessed whether NSAID use was associated with lower breast cancer risk among patients with BBD.

Participants were postmenopausal women in the Cancer Prevention Study-II (CPS-II), a prospective study of cancer incidence and mortality, who completed follow-up surveys in 1997 with follow-up through June 30, 2015. History of BBD, NSAID use, and covariate data were updated biennially. This analysis included 23,615 patients with BBD and 36,751 patients with non-BBD, including 3,896 incident breast cancers over an average of 12.72 years of follow-up among participants. NSAID use, overall and by formulation, recency, duration, and pills per month was analyzed versus breast cancer risk overall and by BBD status using multivariable-adjusted Cox models; BBD status and NSAID use were modeled as time-dependent exposures.

Patients with BBD who reported using NSAIDs experienced lower breast cancer risk (HR, 0.87; 95% CI, 0.78–0.97), with similar effects for estrogen receptor (ER)-positive breast cancers [HR, 0.85; 95% confidence interval (CI), 0.74–0.97] and ER-negative breast cancers (HR, 0.87; 95% CI, 0.59–1.29); among women without BBD, NSAID use was unrelated to risk (HR, 1.02; 95% CI, 0.92–1.13; Pinteraction = 0.04). Associations stratified by age, obesity, menopausal hormone use, and cardiovascular disease were similar.

Among patients with BBD, NSAID use appears linked to lower breast cancer risk. Further studies to assess the value of NSAID use among patients with BBD are warranted.
Prevention Relevance:
We examined whether NSAID use, a modifiable exposure, is associated with breast cancer risk in postmenopausal women from the Cancer Prevention Study-II with self-reported benign breast disease, an often inflammatory condition associated with higher rates of breast cancer.
Data from Short-term PI3K Inhibition Prevents Breast Cancer in Preclinical Models
Authors: Ku Amy T. , Young Adelaide I.J. , Ibrahim Ahmed Atef , Bu Wen , Jiang Weiyu , Lin Meng , Williams Laterrica C. , McCue Bryant Lee , Miles George , Nagi Chandandeep , Behbod Fariba , Li Yi
Published: April 2023

Abstract
Antiestrogen medication is the only chemoprevention currently available for women at a high risk of developing breast cancer; however, antiestrogen therapy requires years to achieve efficacy and has adverse side effects. Therefore, it is important to develop an efficacious chemoprevention strategy that requires only a short course of treatment. PIK3CA is commonly activated in breast atypical hyperplasia, the known precancerous precursor of breast cancer. Targeting PI3K signaling in these precancerous lesions may offer a new strategy for chemoprevention. Here, we first established a mouse model that mimics the progression from precancerous lesions to breast cancer. Next, we demonstrated that a short-course prophylactic treatment with the clinically approved PI3K inhibitor alpelisib slowed early lesion expansion and prevented cancer formation in this model. Furthermore, we showed that alpelisib suppressed ex vivo expansion of patient-derived atypical hyperplasia. Together, these data indicate that the progression of precancerous breast lesions heavily depends on the PI3K signaling, and that prophylactic targeting of PI3K activity can prevent breast cancer.
Prevention Relevance:
PI3K protein is abnormally high in breast precancerous lesions. This preclinical study demonstrates that the FDA-approved anti-PI3K inhibitor alpelisib can prevent breast cancer and thus warrant future clinical trials in high-risk women.
Data from Validation of an abridged breast cancer risk prediction model for the general population
Authors: Spaeth Erika L. , Dite Gillian S. , Hopper John L. , Allman Richard
Published: April 2023

Abstract
Accurate breast cancer risk prediction could improve risk-reduction paradigms if thoughtfully employed in clinical practice. Identification of at-risk women is the first step in tailoring risk screening and risk-reduction protocols to women’s needs. Using the UK Biobank, we validated a simple risk model to predict breast cancer risk in the general population. Our simple breast cancer risk (BRISK) model integrates a combination of impactful breast cancer-associated risk factors including extended family history and polygenic risk allowing for the removal of moderate factors currently found in comprehensive traditional models. Using two versions of BRISK, differing by 77-SNP versus 313-SNP polygenic risk score integration, we found improved discrimination and risk categorization of both BRISK models compared to one of the most well-known models, the Breast Cancer Risk Assessment Tool (BRCAT). Over a five-year period, at-risk women classified ≥3% 5-year risk by BRISK had a 1.829 (95% CI = 1.710, 1.956) times increased incidence of breast cancer compared to the population, which was higher than the 1.413 (95% CI = 1.217 to 1.640) times increased incidence for women classified ≥3% by BCRAT.
Supplementary Figure 1 from A Central Role for RAF→MEK→ERK Signaling in the Genesis of Pancreatic Ductal Adenocarcinoma
Authors: Collisson Eric A. , Trejo Christy L. , Silva Jillian M. , Gu Shenda , Korkola James E. , Heiser Laura M. , Charles Roch-Philippe , Rabinovich Brian A. , Hann Byron , Dankort David , Spellman Paul T. , Phillips Wayne A. , Gray Joe W. , McMahon Martin
Published: April 2023

PDF file - 578K, Characterization of a new, syngeneic, orthotopic mouse model of PDA
Supplementary Table 1 from Functional Metabolic Screen Identifies 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 4 as an Important Regulator of Prostate Cancer Cell Survival
Authors: Ros Susana , Santos Claudio R. , Moco Sofia , Baenke Franziska , Kelly Gavin , Howell Michael , Zamboni Nicola , Schulze Almut
Published: April 2023

PDF file - 73
Supplementary Figure 1 from Functional Metabolic Screen Identifies 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 4 as an Important Regulator of Prostate Cancer Cell Survival
Authors: Ros Susana , Santos Claudio R. , Moco Sofia , Baenke Franziska , Kelly Gavin , Howell Michael , Zamboni Nicola , Schulze Almut
Published: April 2023

PDF file - 378K
Supplementary Table 3 from Proteomic Profiling Identifies Dysregulated Pathways in Small Cell Lung Cancer and Novel Therapeutic Targets Including PARP1
Authors: Byers Lauren Averett , Wang Jing , Nilsson Monique B. , Fujimoto Junya , Saintigny Pierre , Yordy John , Giri Uma , Peyton Michael , Fan You Hong , Diao Lixia , Masrorpour Fatemeh , Shen Li , Liu Wenbin , Duchemann Boris , Tumula Praveen , Bhardwaj Vikas , Welsh James , Weber Stephanie , Glisson Bonnie S. , Kalhor Neda , Wistuba Ignacio I. , Girard Luc , Lippman Scott M. , Mills Gordon B. , Coombes Kevin R. , Weinstein John N. , Minna John D. , Heymach John V.
Published: April 2023

PDF file, 83K, Proteins with ≥1.2-fold differential expression between small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC).
Supplementary Figures 1-10 from Loss of 53BP1 Causes PARP Inhibitor Resistance in Brca1-Mutated Mouse Mammary Tumors
Authors: Jaspers Janneke E. , Kersbergen Ariena , Boon Ute , Sol Wendy , van Deemter Liesbeth , Zander Serge A. , Drost Rinske , Wientjens Ellen , Ji Jiuping , Aly Amal , Doroshow James H. , Cranston Aaron , Martin Niall M.B. , Lau Alan , O'Connor Mark J. , Ganesan Shridar , Borst Piet , Jonkers Jos , Rottenberg Sven
Published: April 2023

PDF file - 1.2MB, This file contains additional data on tumor responses to olaparib treatment (Fig. S1 and S2), pH2AX stainings on treated and untreated tumors (Fig. S3), analysis of mutations in 53BP1 (Fig. S4 and S7B), characterization of cell lines (Fig. S5), RAD51 and 53BP1 IRIFs in tumors and cell lines (Fig. S6 and S7), 53BP1 in topotecan-resistant tumors (Fig. S8) and tumor responses to AZD2461 treatment (Fig. S9 and S10).
Supplementary Methods and Figure Legend from Proteomic Profiling Identifies Dysregulated Pathways in Small Cell Lung Cancer and Novel Therapeutic Targets Including PARP1
Authors: Byers Lauren Averett , Wang Jing , Nilsson Monique B. , Fujimoto Junya , Saintigny Pierre , Yordy John , Giri Uma , Peyton Michael , Fan You Hong , Diao Lixia , Masrorpour Fatemeh , Shen Li , Liu Wenbin , Duchemann Boris , Tumula Praveen , Bhardwaj Vikas , Welsh James , Weber Stephanie , Glisson Bonnie S. , Kalhor Neda , Wistuba Ignacio I. , Girard Luc , Lippman Scott M. , Mills Gordon B. , Coombes Kevin R. , Weinstein John N. , Minna John D. , Heymach John V.
Published: April 2023

PDF file, 142K.
Supplementary Figure 3 from Proteomic Profiling Identifies Dysregulated Pathways in Small Cell Lung Cancer and Novel Therapeutic Targets Including PARP1
Authors: Byers Lauren Averett , Wang Jing , Nilsson Monique B. , Fujimoto Junya , Saintigny Pierre , Yordy John , Giri Uma , Peyton Michael , Fan You Hong , Diao Lixia , Masrorpour Fatemeh , Shen Li , Liu Wenbin , Duchemann Boris , Tumula Praveen , Bhardwaj Vikas , Welsh James , Weber Stephanie , Glisson Bonnie S. , Kalhor Neda , Wistuba Ignacio I. , Girard Luc , Lippman Scott M. , Mills Gordon B. , Coombes Kevin R. , Weinstein John N. , Minna John D. , Heymach John V.
Published: April 2023

PDF file, 81K, Effect of PARP inhibition in combination with standard chemotherapy.
Supplementary Figure 8 from Noncovalent Wild-type–Sparing Inhibitors of EGFR T790M
Authors: Lee Ho-June , Schaefer Gabriele , Heffron Timothy P. , Shao Lily , Ye Xiaofen , Sideris Steve , Malek Shiva , Chan Emily , Merchant Mark , La Hank , Ubhayakar Savita , Yauch Robert L. , Pirazzoli Valentina , Politi Katerina , Settleman Jeff
Published: April 2023

PDF file - 78K, Efficacy of PKC412 on tumor growth and signaling in EGFRL858R+T790M transgenic mice.
Supplementary Figure 1 from Proteomic Profiling Identifies Dysregulated Pathways in Small Cell Lung Cancer and Novel Therapeutic Targets Including PARP1
Authors: Byers Lauren Averett , Wang Jing , Nilsson Monique B. , Fujimoto Junya , Saintigny Pierre , Yordy John , Giri Uma , Peyton Michael , Fan You Hong , Diao Lixia , Masrorpour Fatemeh , Shen Li , Liu Wenbin , Duchemann Boris , Tumula Praveen , Bhardwaj Vikas , Welsh James , Weber Stephanie , Glisson Bonnie S. , Kalhor Neda , Wistuba Ignacio I. , Girard Luc , Lippman Scott M. , Mills Gordon B. , Coombes Kevin R. , Weinstein John N. , Minna John D. , Heymach John V.
Published: April 2023

PDF file, 125K, Western blot of total PARP1.
Supplementary Figure 6 from Noncovalent Wild-type–Sparing Inhibitors of EGFR T790M
Authors: Lee Ho-June , Schaefer Gabriele , Heffron Timothy P. , Shao Lily , Ye Xiaofen , Sideris Steve , Malek Shiva , Chan Emily , Merchant Mark , La Hank , Ubhayakar Savita , Yauch Robert L. , Pirazzoli Valentina , Politi Katerina , Settleman Jeff
Published: April 2023

PDF file - 21K, Body weight measurement for EGFR T790M xenografts.
Supplementary Figure 4 from Noncovalent Wild-type–Sparing Inhibitors of EGFR T790M
Authors: Lee Ho-June , Schaefer Gabriele , Heffron Timothy P. , Shao Lily , Ye Xiaofen , Sideris Steve , Malek Shiva , Chan Emily , Merchant Mark , La Hank , Ubhayakar Savita , Yauch Robert L. , Pirazzoli Valentina , Politi Katerina , Settleman Jeff
Published: April 2023

PDF file - 142K, EGFR sequencing of the PC-9 ER clone.
Supplementary Figure S6 from Hypoxia Induces Phenotypic Plasticity and Therapy Resistance in Melanoma via the Tyrosine Kinase Receptors ROR1 and ROR2
Authors: O'Connell Michael P. , Marchbank Katie , Webster Marie R. , Valiga Alexander A. , Kaur Amanpreet , Vultur Adina , Li Ling , Herlyn Meenhard , Villanueva Jessie , Liu Qin , Yin Xiangfan , Widura Sandy , Nelson Janelle , Ruiz Nivia , Camilli Tura C. , Indig Fred E. , Flaherty Keith T. , Wargo Jennifer A. , Frederick Dennie T. , Cooper Zachary A. , Nair Suresh , Amaravadi Ravi K. , Schuchter Lynn M. , Karakousis Giorgos C. , Xu Wei , Xu Xiaowei , Weeraratna Ashani T.
Published: April 2023

PDF file 165K, Decreases in ROR2 expression increase tumor cell sensitivity to BRAF inhibitors
Supplementary Figure S5 from Hypoxia Induces Phenotypic Plasticity and Therapy Resistance in Melanoma via the Tyrosine Kinase Receptors ROR1 and ROR2
Authors: O'Connell Michael P. , Marchbank Katie , Webster Marie R. , Valiga Alexander A. , Kaur Amanpreet , Vultur Adina , Li Ling , Herlyn Meenhard , Villanueva Jessie , Liu Qin , Yin Xiangfan , Widura Sandy , Nelson Janelle , Ruiz Nivia , Camilli Tura C. , Indig Fred E. , Flaherty Keith T. , Wargo Jennifer A. , Frederick Dennie T. , Cooper Zachary A. , Nair Suresh , Amaravadi Ravi K. , Schuchter Lynn M. , Karakousis Giorgos C. , Xu Wei , Xu Xiaowei , Weeraratna Ashani T.
Published: April 2023

PDF file 234K, WNT5A induced degradation of ?-catenin requires SIAH2
Supplementary Figure 1 from Noncovalent Wild-type–Sparing Inhibitors of EGFR T790M
Authors: Lee Ho-June , Schaefer Gabriele , Heffron Timothy P. , Shao Lily , Ye Xiaofen , Sideris Steve , Malek Shiva , Chan Emily , Merchant Mark , La Hank , Ubhayakar Savita , Yauch Robert L. , Pirazzoli Valentina , Politi Katerina , Settleman Jeff
Published: April 2023

PDF file - 528K, G�6976 inhibits EGFR mutant NSCLC cells independently of PKC inhibition.
Supplementary Figure S4 from Hypoxia Induces Phenotypic Plasticity and Therapy Resistance in Melanoma via the Tyrosine Kinase Receptors ROR1 and ROR2
Authors: O'Connell Michael P. , Marchbank Katie , Webster Marie R. , Valiga Alexander A. , Kaur Amanpreet , Vultur Adina , Li Ling , Herlyn Meenhard , Villanueva Jessie , Liu Qin , Yin Xiangfan , Widura Sandy , Nelson Janelle , Ruiz Nivia , Camilli Tura C. , Indig Fred E. , Flaherty Keith T. , Wargo Jennifer A. , Frederick Dennie T. , Cooper Zachary A. , Nair Suresh , Amaravadi Ravi K. , Schuchter Lynn M. , Karakousis Giorgos C. , Xu Wei , Xu Xiaowei , Weeraratna Ashani T.
Published: April 2023

PDF file 103K, Decreasing ROR1 increases ROR2 and decreases proliferation in vivo
Supplementary Figure 6 from Preexisting MEK1 Exon 3 Mutations in V600E/KBRAF Melanomas Do Not Confer Resistance to BRAF Inhibitors
Authors: Shi Hubing , Moriceau Gatien , Kong Xiangju , Koya Richard C. , Nazarian Ramin , Pupo Gulietta M. , Bacchiocchi Antonella , Dahlman Kimberly B. , Chmielowski Bartosz , Sosman Jeffrey A. , Halaban Ruth , Kefford Richard F. , Long Georgina V. , Ribas Antoni , Lo Roger S.
Published: April 2023

PDF file - 181K, WTMEK and P124SMEK activated by V600EB-RAF display similar in vitro kinase activities toward recombinant ERK1. HEK293T cells were transfected with vector, FLAG-MEK1 WT, or FLAG-MEK1 P124S in the absence or presence of co-transfected V600EB-RAF. Cells were lysed and exogenous MEK1 immunoprecipitated (IP) using isotype (I) control or anti-FLAG (F) antibody (ab), washed, and subjected to in vitro kinase assay. Pre-IP lysates were immunoblotted for FLAG levels. After the kinase reaction, the supernatant (sup) or ab-bead fractions were mixed with denaturing loading buffers, fractionated and immunoblotted against indicated phospho- or total protein levels (rERK, recombinant ERK).
Supplementary Table 1 from Cancer-Specific Requirement for BUB1B/BUBR1 in Human Brain Tumor Isolates and Genetically Transformed Cells
Authors: Ding Yu , Hubert Christopher G. , Herman Jacob , Corrin Philip , Toledo Chad M. , Skutt-Kakaria Kyobi , Vazquez Julio , Basom Ryan , Zhang Bin , Risler Jennifer K. , Pollard Steven M. , Nam Do-Hyun , Delrow Jeffery J. , Zhu Jun , Lee Jeongwu , DeLuca Jennifer , Olson James M. , Paddison Patrick J.
Published: April 2023

XLS file - 42K, Candidate genes differentially required for expansion of G166-BTICs
Supplementary Figure 5 from PI3K Inhibition Impairs BRCA1/2 Expression and Sensitizes BRCA-Proficient Triple-Negative Breast Cancer to PARP Inhibition
Authors: Ibrahim Yasir H. , García-García Celina , Serra Violeta , He Lei , Torres-Lockhart Kristine , Prat Aleix , Anton Pilar , Cozar Patricia , Guzmán Marta , Grueso Judit , Rodríguez Olga , Calvo Maria Teresa , Aura Claudia , Díez Orland , Rubio Isabel T. , Pérez José , Rodón Jordi , Cortés Javier , Ellisen Leif W. , Scaltriti Maurizio , Baselga José
Published: April 2023

PDF file - 162K, Western blot of cell lysates from MDA-MB-468 or PDC44 cells treated with 750nM and 500nM BKM120 respectively for 4 days using the indicated antibodies
Supplementary Figure 3 from PI3K Inhibition Impairs BRCA1/2 Expression and Sensitizes BRCA-Proficient Triple-Negative Breast Cancer to PARP Inhibition
Authors: Ibrahim Yasir H. , García-García Celina , Serra Violeta , He Lei , Torres-Lockhart Kristine , Prat Aleix , Anton Pilar , Cozar Patricia , Guzmán Marta , Grueso Judit , Rodríguez Olga , Calvo Maria Teresa , Aura Claudia , Díez Orland , Rubio Isabel T. , Pérez José , Rodón Jordi , Cortés Javier , Ellisen Leif W. , Scaltriti Maurizio , Baselga José
Published: April 2023

PDF file - 301K, Combined PIK3CA siRNA and PARP suppression in TNBC cell lines
Supplementary Figure 8 from Cancer-Specific Requirement for BUB1B/BUBR1 in Human Brain Tumor Isolates and Genetically Transformed Cells
Authors: Ding Yu , Hubert Christopher G. , Herman Jacob , Corrin Philip , Toledo Chad M. , Skutt-Kakaria Kyobi , Vazquez Julio , Basom Ryan , Zhang Bin , Risler Jennifer K. , Pollard Steven M. , Nam Do-Hyun , Delrow Jeffery J. , Zhu Jun , Lee Jeongwu , DeLuca Jennifer , Olson James M. , Paddison Patrick J.
Published: April 2023

PDF file - 340K, Effects of BUB1B knockdown on in human astrocytes, RasV12 transformed astrocytes, Hela cells and RPE-1 cells
Supplementary Figure 3 from Cancer-Specific Requirement for BUB1B/BUBR1 in Human Brain Tumor Isolates and Genetically Transformed Cells
Authors: Ding Yu , Hubert Christopher G. , Herman Jacob , Corrin Philip , Toledo Chad M. , Skutt-Kakaria Kyobi , Vazquez Julio , Basom Ryan , Zhang Bin , Risler Jennifer K. , Pollard Steven M. , Nam Do-Hyun , Delrow Jeffery J. , Zhu Jun , Lee Jeongwu , DeLuca Jennifer , Olson James M. , Paddison Patrick J.
Published: April 2023

PDF file - 74K, BUB1B and other mitotic checkpoint genes are up-regulated in BTIC isolates and Ras- transformed astrocytes
Supplementary Figure 4 from Coordinate Direct Input of Both KRAS and IGF1 Receptor to Activation of PI3 kinase in KRAS-Mutant Lung Cancer
Authors: Molina-Arcas Miriam , Hancock David C. , Sheridan Clare , Kumar Madhu S. , Downward Julian
Published: April 2023

Supplementary Figure 4 - PDF file 391K, Effects of combining MEK and IGF1R inhibitors on signal transduction pathways in NSCLC cell lines
Supplementary Figure 2 from Coordinate Direct Input of Both KRAS and IGF1 Receptor to Activation of PI3 kinase in KRAS-Mutant Lung Cancer
Authors: Molina-Arcas Miriam , Hancock David C. , Sheridan Clare , Kumar Madhu S. , Downward Julian
Published: April 2023

Supplementary Figure 2 - PDF file 719K, Effects of MEK inhibitors on signal transduction pathways in NSCLC cell lines
Supplementary Figures 1 - 9 from MicroRNAs Reprogram Normal Fibroblasts into Cancer-Associated Fibroblasts in Ovarian Cancer
Authors: Mitra Anirban K. , Zillhardt Marion , Hua Youjia , Tiwari Payal , Murmann Andrea E. , Peter Marcus E. , Lengyel Ernst
Published: April 2023

PDF file - 1778K, Data on fibroblast characterization, array and transfection validation, function role of individual microRNAs and mouse xenograft images.
Supplementary Figure 1 from A Bioluminescent Transposon Reporter-Trap Identifies Tumor-Specific Microenvironment-Induced Promoters in Salmonella for Conditional Bacterial-Based Tumor Therapy
Authors: Flentie Kelly , Kocher Brandon , Gammon Seth T. , Novack Deborah V. , McKinney Jeffrey S. , Piwnica-Worms David
Published: April 2023

PDF file - 216K, Activated genes are not essential for Salmonella tumor localization.
Supplementary Table 1 from Activating HER2 Mutations in HER2 Gene Amplification Negative Breast Cancer
Authors: Bose Ron , Kavuri Shyam M. , Searleman Adam C. , Shen Wei , Shen Dong , Koboldt Daniel C. , Monsey John , Goel Nicholas , Aronson Adam B. , Li Shunqiang , Ma Cynthia X. , Ding Li , Mardis Elaine R. , Ellis Matthew J.
Published: April 2023

PDF file - 26K, HER2 somatic mutations described in prior breast cancer sequencing studies
Supplementary Figure 3 from Activating HER2 Mutations in HER2 Gene Amplification Negative Breast Cancer
Authors: Bose Ron , Kavuri Shyam M. , Searleman Adam C. , Shen Wei , Shen Dong , Koboldt Daniel C. , Monsey John , Goel Nicholas , Aronson Adam B. , Li Shunqiang , Ma Cynthia X. , Ding Li , Mardis Elaine R. , Ellis Matthew J.
Published: April 2023

PDF file - 60K, HER2 L755S is sensitive to the irreversible inhibitor, canertinib
Supplementary Figure 4 from First-in-Human Trial of a STAT3 Decoy Oligonucleotide in Head and Neck Tumors: Implications for Cancer Therapy
Authors: Sen Malabika , Thomas Sufi M. , Kim Seungwon , Yeh Joanne I. , Ferris Robert L. , Johnson Jonas T. , Duvvuri Umamaheswar , Lee Jessica , Sahu Nivedita , Joyce Sonali , Freilino Maria L. , Shi Haibin , Li Changyou , Ly Danith , Rapireddy Srinivas , Etter Jonathan P. , Li Pui-Kai , Wang Lin , Chiosea Simion , Seethala Raja R. , Gooding William E. , Chen Xiaomin , Kaminski Naftali , Pandit Kusum , Johnson Daniel E. , Grandis Jennifer R.
Published: April 2023

PDF file - 1.2MB, Modified STAT3 decoys bind to pSTAT3 protein with similar affinity as the parental STAT3 decoy
Supplementary Tables 1-4 from ERα-Dependent E2F Transcription Can Mediate Resistance to Estrogen Deprivation in Human Breast Cancer
Authors: Miller Todd W. , Balko Justin M. , Fox Emily M. , Ghazoui Zara , Dunbier Anita , Anderson Helen , Dowsett Mitch , Jiang Aixiang , Smith R. Adam , Maira Sauveur-Michel , Manning H. Charles , González-Angulo Ana M. , Mills Gordon B. , Higham Catherine , Chanthaphaychith Siprachanh , Kuba Maria G. , Miller William R. , Shyr Yu , Arteaga Carlos L.
Published: April 2023

XLS file - 44K
Supplementary Figure 1 from First-in-Human Trial of a STAT3 Decoy Oligonucleotide in Head and Neck Tumors: Implications for Cancer Therapy
Authors: Sen Malabika , Thomas Sufi M. , Kim Seungwon , Yeh Joanne I. , Ferris Robert L. , Johnson Jonas T. , Duvvuri Umamaheswar , Lee Jessica , Sahu Nivedita , Joyce Sonali , Freilino Maria L. , Shi Haibin , Li Changyou , Ly Danith , Rapireddy Srinivas , Etter Jonathan P. , Li Pui-Kai , Wang Lin , Chiosea Simion , Seethala Raja R. , Gooding William E. , Chen Xiaomin , Kaminski Naftali , Pandit Kusum , Johnson Daniel E. , Grandis Jennifer R.
Published: April 2023

PDF file - 70K, Lack of anti-tumor effects of systemically administered parental STAT3 decoy
Supplementary Table 4 from Janus Kinase 3–Activating Mutations Identified in Natural Killer/T-cell Lymphoma
Authors: Koo Ghee Chong , Tan Soo Yong , Tang Tiffany , Poon Song Ling , Allen George E. , Tan Leonard , Chong Soo Ching , Ong Whee Sze , Tay Kevin , Tao Miriam , Quek Richard , Loong Susan , Yeoh Kheng-Wei , Yap Swee Peng , Lee Kuo Ann , Lim Lay Cheng , Tan Daryl , Goh Christopher , Cutcutache Ioana , Yu Willie , Young Ng Cedric Chuan , Rajasegaran Vikneswari , Heng Hong Lee , Gan Anna , Ong Choon Kiat , Rozen Steve , Tan Patrick , Teh Bin Tean , Lim Soon Thye
Published: April 2023

PDF file - 74K, Primer sets used for Sanger sequencing and HRM analysis
Supplementary Table 2 from Janus Kinase 3–Activating Mutations Identified in Natural Killer/T-cell Lymphoma
Authors: Koo Ghee Chong , Tan Soo Yong , Tang Tiffany , Poon Song Ling , Allen George E. , Tan Leonard , Chong Soo Ching , Ong Whee Sze , Tay Kevin , Tao Miriam , Quek Richard , Loong Susan , Yeoh Kheng-Wei , Yap Swee Peng , Lee Kuo Ann , Lim Lay Cheng , Tan Daryl , Goh Christopher , Cutcutache Ioana , Yu Willie , Young Ng Cedric Chuan , Rajasegaran Vikneswari , Heng Hong Lee , Gan Anna , Ong Choon Kiat , Rozen Steve , Tan Patrick , Teh Bin Tean , Lim Soon Thye
Published: April 2023

PDF file - 110K, Non-synonymous somatic mutations identified in the Discovery set of four NKTCL cases
Supplementary Table 6 from TYK2–STAT1–BCL2 Pathway Dependence in T-cell Acute Lymphoblastic Leukemia
Authors: Sanda Takaomi , Tyner Jeffrey W. , Gutierrez Alejandro , Ngo Vu N. , Glover Jason , Chang Bill H. , Yost Arla , Ma Wenxue , Fleischman Angela G. , Zhou Wenjun , Yang Yandan , Kleppe Maria , Ahn Yebin , Tatarek Jessica , Kelliher Michelle A. , Neuberg Donna S. , Levine Ross L. , Moriggl Richard , Müller Mathias , Gray Nathanael S. , Jamieson Catriona H.M. , Weng Andrew P. , Staudt Louis M. , Druker Brian J. , Look A. Thomas
Published: April 2023

XLSX file - 23K, Clinical, biologic and molecular characteristics of the T-ALL patient samples analyzed. See separate file.
Supplementary Figure 3 from GSK-3α Promotes Oncogenic KRAS Function in Pancreatic Cancer via TAK1–TAB Stabilization and Regulation of Noncanonical NF-κB
Authors: Bang Deepali , Wilson Willie , Ryan Meagan , Yeh Jen Jen , Baldwin Albert S.
Published: April 2023

PDF file - 113K, TAK1 inhibition decreases cell proliferation in Kras+ cells. Indicated cell lines were seeded in E-plate-16 (Roche) at 3000 cells/well/100μl. 24hours after plating, cells were treated with TAK1 inhibitor 5Z-7-oxozaenol (0.625μM), or vehicle control, DMSO. Cell impedance was measured every 2 hours for the entire course of experiment using RTCA.
Supplementary Figure 10 from Discovery of a Mutant-Selective Covalent Inhibitor of EGFR that Overcomes T790M-Mediated Resistance in NSCLC
Authors: Walter Annette O. , Sjin Robert Tjin Tham , Haringsma Henry J. , Ohashi Kadoaki , Sun Jing , Lee Kwangho , Dubrovskiy Aleksandr , Labenski Matthew , Zhu Zhendong , Wang Zhigang , Sheets Michael , St Martin Thia , Karp Russell , van Kalken Dan , Chaturvedi Prasoon , Niu Deqiang , Nacht Mariana , Petter Russell C. , Westlin William , Lin Kevin , Jaw-Tsai Sarah , Raponi Mitch , Van Dyke Terry , Etter Jeff , Weaver Zoe , Pao William , Singh Juswinder , Simmons Andrew D. , Harding Thomas C. , Allen Andrew
Published: April 2023

Supplementary Figure 10 - PDF file 333K, Analysis of multiple EGFR-related signaling pathways in parental NCI-H1975 and COR resistant clones by Western blotting
Supplementary Methods from The Androgen-Regulated Protease TMPRSS2 Activates a Proteolytic Cascade Involving Components of the Tumor Microenvironment and Promotes Prostate Cancer Metastasis
Authors: Lucas Jared M. , Heinlein Cynthia , Kim Tom , Hernandez Susana A. , Malik Muzdah S. , True Lawrence D. , Morrissey Colm , Corey Eva , Montgomery Bruce , Mostaghel Elahe , Clegg Nigel , Coleman Ilsa , Brown Christopher M. , Schneider Eric L. , Craik Charles , Simon Julian A. , Bedalov Antonio , Nelson Peter S.
Published: April 2023

Supplementary Methods from The Androgen-Regulated Protease TMPRSS2 Activates a Proteolytic Cascade Involving Components of the Tumor Microenvironment and Promotes Prostate Cancer Metastasis
Table S2 from PDK1 Signaling Toward PLK1–MYC Activation Confers Oncogenic Transformation, Tumor-Initiating Cell Activation, and Resistance to mTOR-Targeted Therapy
Authors: Tan Jing , Li Zhimei , Lee Puay Leng , Guan Peiyong , Aau Mei Yee , Lee Shuet Theng , Feng Min , Lim Cheryl Zihui , Lee Eric Yong Jing , Wee Zhen Ning , Lim Yaw Chyn , Karuturi R.K. Murthy , Yu Qiang
Published: April 2023

Table S2 - XLS file 203K, Supplementary table 2 shows the expression profiles of Myc-regulated genes in HEK-Vector, -PDK1, -Myc and -E545K cells
Supplementary Table S1 from A Novel AKT1 Mutant Amplifies an Adaptive Melanoma Response to BRAF Inhibition
Authors: Shi Hubing , Hong Aayoung , Kong Xiangju , Koya Richard C. , Song Chunying , Moriceau Gatien , Hugo Willy , Yu Clarissa C. , Ng Charles , Chodon Thinle , Scolyer Richard A. , Kefford Richard F. , Ribas Antoni , Long Georgina V. , Lo Roger S.
Published: April 2023

PDF file 47K, This table provides clinical data for the patient donors
Supplementary Figure S4 from Suppression of Early Hematogenous Dissemination of Human Breast Cancer Cells to Bone Marrow by Retinoic Acid–Induced 2
Authors: Werner Stefan , Brors Benedikt , Eick Julia , Marques Elsa , Pogenberg Vivian , Parret Annabel , Kemming Dirk , Wood Antony W. , Edgren Henrik , Neubauer Hans , Streichert Thomas , Riethdorf Sabine , Bedi Upasana , Baccelli Irène , Jücker Manfred , Eils Roland , Fehm Tanja , Trumpp Andreas , Johnsen Steven A. , Klefström Juha , Wilmanns Matthias , Müller Volkmar , Pantel Klaus , Wikman Harriet
Published: April 2023

Supplementary Figure S4. Data base analysis of correlation between RAI2 and ESR1 mRNA expression.
Supplementary Movie S1 from An In Vivo Functional Screen Identifies ST6GalNAc2 Sialyltransferase as a Breast Cancer Metastasis Suppressor
Authors: Murugaesu Nirupa , Iravani Marjan , van Weverwijk Antoinette , Ivetic Aleksandar , Johnson Damian A. , Antonopoulos Aristotelis , Fearns Antony , Jamal-Hanjani Mariam , Sims David , Fenwick Kerry , Mitsopoulos Costas , Gao Qiong , Orr Nick , Zvelebil Marketa , Haslam Stuart M. , Dell Anne , Yarwood Helen , Lord Christopher J. , Ashworth Alan , Isacke Clare M.
Published: April 2023

MOV file 2346K, Video showing dynamic flow adhesion assays of ZR75.1 shNTC and shST6 cells on a HUVEC monolayer
Supplementary Figure S4 from An In Vivo Functional Screen Identifies ST6GalNAc2 Sialyltransferase as a Breast Cancer Metastasis Suppressor
Authors: Murugaesu Nirupa , Iravani Marjan , van Weverwijk Antoinette , Ivetic Aleksandar , Johnson Damian A. , Antonopoulos Aristotelis , Fearns Antony , Jamal-Hanjani Mariam , Sims David , Fenwick Kerry , Mitsopoulos Costas , Gao Qiong , Orr Nick , Zvelebil Marketa , Haslam Stuart M. , Dell Anne , Yarwood Helen , Lord Christopher J. , Ashworth Alan , Isacke Clare M.
Published: April 2023

PDF file 174K, Additional characterization of the 4T1-Luc cells in lung retention assays
Supplementary Figure S3 from An In Vivo Functional Screen Identifies ST6GalNAc2 Sialyltransferase as a Breast Cancer Metastasis Suppressor
Authors: Murugaesu Nirupa , Iravani Marjan , van Weverwijk Antoinette , Ivetic Aleksandar , Johnson Damian A. , Antonopoulos Aristotelis , Fearns Antony , Jamal-Hanjani Mariam , Sims David , Fenwick Kerry , Mitsopoulos Costas , Gao Qiong , Orr Nick , Zvelebil Marketa , Haslam Stuart M. , Dell Anne , Yarwood Helen , Lord Christopher J. , Ashworth Alan , Isacke Clare M.
Published: April 2023

PDF file 60K, Characterization of the MDA-MB-231 cells stably expressing vector or mouse ST6GalNAc2
Supplementary Figure S1 from An In Vivo Functional Screen Identifies ST6GalNAc2 Sialyltransferase as a Breast Cancer Metastasis Suppressor
Authors: Murugaesu Nirupa , Iravani Marjan , van Weverwijk Antoinette , Ivetic Aleksandar , Johnson Damian A. , Antonopoulos Aristotelis , Fearns Antony , Jamal-Hanjani Mariam , Sims David , Fenwick Kerry , Mitsopoulos Costas , Gao Qiong , Orr Nick , Zvelebil Marketa , Haslam Stuart M. , Dell Anne , Yarwood Helen , Lord Christopher J. , Ashworth Alan , Isacke Clare M.
Published: April 2023

PDF file 149K, In vivo validation of 3 hits identified in the screen (Mre11a, Fen1, Wwc1)
Supplementary Figure 7 from DNA-Damage Response during Mitosis Induces Whole-Chromosome Missegregation
Authors: Bakhoum Samuel F. , Kabeche Lilian , Murnane John P. , Zaki Bassem I. , Compton Duane A.
Published: April 2023

Control and irradiated (12 Gy) RPE1 cells stained for Aurora-B (A), p-Hec1 (C), p-Histone H3 (E), and p-Cenp-A (G) in green, and DNA (blue). Centromeres (in red) were stained using anti-centromere antibody (CREST). Insets in A show centromere and Aurora B staining at higher magnifications. Relative fluorescence intensity of p-Hec1 (B), p-Histone H3 (D), and p-Cenp-A (F) compared to centromere staining. Bars represent mean {plus minus} SD, n = 10 cells, >300 kinetochores.
Supplementary Figure 4 from DNA-Damage Response during Mitosis Induces Whole-Chromosome Missegregation
Authors: Bakhoum Samuel F. , Kabeche Lilian , Murnane John P. , Zaki Bassem I. , Compton Duane A.
Published: April 2023

IR does not significantly perturb the spindle assembly checkpoint (SAC). A, Experimental schema of assessing the SAC after IR. Noc, Nocodazole. Bar graph depicting mitotic indices as a function of IR dose of Nocodazole-arrested cells 1 hour after irradiation; ns, p>0.2, Ï‡2-test, n=187-523 cells. B, Experimental schema of assessing the SAC after Doxorubicin exposure. Noc, Nocodazole; Doxo, Doxorubicin. Graph depicting the number of mitotic cells after mitotic shakeoff in the absence of nocodazole (control), or in the presence of nocodazole only (Noc), or Nocodazole after a 1-hour exposure to Doxorubicin (Noc + Doxo).
Supplementary Data from Acetyl-CoA Metabolism Supports Multistep Pancreatic Tumorigenesis
Authors: Carrer Alessandro , Trefely Sophie , Zhao Steven , Campbell Sydney L. , Norgard Robert J. , Schultz Kollin C. , Sidoli Simone , Parris Joshua L.D. , Affronti Hayley C. , Sivanand Sharanya , Egolf Shaun , Sela Yogev , Trizzino Marco , Gardini Alessandro , Garcia Benjamin A. , Snyder Nathaniel W. , Stanger Ben Z. , Wellen Kathryn E.
Published: April 2023

Figures S1-S7 and Table S1
Data from DEAR1 Is a Chromosome 1p35 Tumor Suppressor and Master Regulator of TGF-β–Driven Epithelial–Mesenchymal Transition
Authors: Chen Nanyue , Balasenthil Seetharaman , Reuther Jacquelyn , Frayna Aileen , Wang Ying , Chandler Dawn S. , Abruzzo Lynne V. , Rashid Asif , Rodriguez Jaime , Lozano Guillermina , Cao Yu , Lokken Erica , Chen Jinyun , Frazier Marsha L. , Sahin Aysegul A. , Wistuba Ignacio I. , Sen Subrata , Lott Steven T. , Killary Ann McNeill
Published: April 2023

Abstract
Deletion of chromosome 1p35 is a common event in epithelial malignancies. We report that DEAR1 (annotated as TRIM62) is a chromosome 1p35 tumor suppressor that undergoes mutation, copy number variation, and loss of expression in human tumors. Targeted disruption in the mouse recapitulates this human tumor spectrum, with both Dear1−/− and Dear1+/− mice developing primarily epithelial adenocarcinomas and lymphoma with evidence of metastasis in a subset of mice. DEAR1 loss of function in the presence of TGF-β results in failure of acinar morphogenesis, upregulation of epithelial–mesenchymal transition (EMT) markers, anoikis resistance, migration, and invasion. Furthermore, DEAR1 blocks TGF-β–SMAD3 signaling, resulting in decreased nuclear phosphorylated SMAD3 by binding to and promoting the ubiquitination of SMAD3, the major effector of TGF-β–induced EMT. Moreover, DEAR1 loss increases levels of SMAD3 downstream effectors SNAIL1 and SNAIL2, with genetic alteration of DEAR1/SNAIL2 serving as prognostic markers of overall poor survival in a cohort of 889 cases of invasive breast cancer.

Significance: Cumulative results provide compelling evidence that DEAR1 is a critical tumor suppressor involved in multiple human cancers and provide a novel paradigm for regulation of TGF-β–induced EMT through DEAR1′s regulation of SMAD3 protein levels. DEAR1 loss of function has important therapeutic implications for targeted therapies aimed at the TGF-β–SMAD3 pathway. Cancer Discov; 3(10); 1172–89. ©2013 AACR.

This article is highlighted in the In This Issue feature, p. 1083
Data from FGFR-Mediated Reactivation of MAPK Signaling Attenuates Antitumor Effects of Imatinib in Gastrointestinal Stromal Tumors
Authors: Li Fang , Huynh Hung , Li Xiaoyan , Ruddy David A. , Wang Youzhen , Ong Richard , Chow Pierce , Qiu Shumei , Tam Angela , Rakiec Daniel P. , Schlegel Robert , Monahan John E. , Huang Alan
Published: April 2023

Abstract
Activating mutations in either KIT or PDGFRA are present in approximately 90% of gastrointestinal stromal tumors (GIST). Although treatment with the KIT and PDGFR inhibitor imatinib can control advanced disease in about 80% of GIST patients, the beneficial effect is not durable. Here, we report that ligands from the FGF family reduced the effectiveness of imatinib in GIST cells, and FGF2 and FGFR1 are highly expressed in all primary GIST samples examined. The combination of KIT and FGFR inhibition showed increased growth inhibition in imatinib-sensitive GIST cell lines and improved efficacy in patient-derived GIST xenografts. In addition, inhibition of MAPK signaling by imatinib was not sustained in GIST cells. An ERK rebound occurred through activation of FGF signaling, and was repressed by FGFR1 inhibition. Downregulation of Sprouty proteins played a role in the imatinib-induced feedback activation of FGF signaling in GIST cells.

Significance: We here show that FGFR-mediated reactivation of the MAPK pathway attenuates the antiproliferation effects of imatinib in GISTs. The imatinib-induced ERK rebound can be repressed by the FGFR inhibitor BGJ398, and combined KIT and FGFR inhibition leads to increased efficacy in vitro and in patient-derived xenografts. Cancer Discov; 5(4); 438–51. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 333
Data from YAP Is Essential for Treg-Mediated Suppression of Antitumor Immunity
Authors: Ni Xuhao , Tao Jinhui , Barbi Joseph , Chen Qian , Park Benjamin V. , Li Zhiguang , Zhang Nailing , Lebid Andriana , Ramaswamy Anjali , Wei Ping , Zheng Ying , Zhang Xuehong , Wu Xingmei , Vignali Paolo , Yang Cui-Ping , Li Huabin , Pardoll Drew , Lu Ling , Pan Duojia , Pan Fan
Published: April 2023

Abstract
Regulatory T cells (Treg) are critical for maintaining self-tolerance and immune homeostasis, but their suppressive function can impede effective antitumor immune responses. FOXP3 is a transcription factor expressed in Tregs that is required for their function. However, the pathways and microenvironmental cues governing FOXP3 expression and Treg function are not completely understood. Herein, we report that YAP, a coactivator of the Hippo pathway, is highly expressed in Tregs and bolsters FOXP3 expression and Treg function in vitro and in vivo. This potentiation stemmed from YAP-dependent upregulation of activin signaling, which amplifies TGFβ/SMAD activation in Tregs. YAP deficiency resulted in dysfunctional Tregs unable to suppress antitumor immunity or promote tumor growth in mice. Chemical YAP antagonism and knockout or blockade of the YAP-regulated activin receptor similarly improved antitumor immunity. Thus, we identify YAP as an unexpected amplifier of a Treg-reinforcing pathway with significant potential as an anticancer immunotherapeutic target.

Significance: Tregs suppress antitumor immunity, and pathways supporting their function can be novel immunotherapy targets. Here, the selective expression of YAP by Tregs, its importance for their function, and its unexpected enhancement of pro-Treg Activin/SMAD signaling are reported, as are validations of potential cancer-fighting antagonists of YAP and its regulatory targets. Cancer Discov; 8(8); 1026–43. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 899
Data from PPT1 Promotes Tumor Growth and Is the Molecular Target of Chloroquine Derivatives in Cancer
Authors: Rebecca Vito W. , Nicastri Michael C. , Fennelly Colin , Chude Cynthia I. , Barber-Rotenberg Julie S. , Ronghe Amruta , McAfee Quentin , McLaughlin Noel P. , Zhang Gao , Goldman Aaron R. , Ojha Rani , Piao Shengfu , Noguera-Ortega Estela , Martorella Alessandra , Alicea Gretchen M. , Lee Jennifer J. , Schuchter Lynn M. , Xu Xiaowei , Herlyn Meenhard , Marmorstein Ronen , Gimotty Phyllis A. , Speicher David W. , Winkler Jeffrey D. , Amaravadi Ravi K.
Published: April 2023

Abstract
Clinical trials repurposing lysosomotropic chloroquine (CQ) derivatives as autophagy inhibitors in cancer demonstrate encouraging results, but the underlying mechanism of action remains unknown. Here, we report a novel dimeric CQ (DC661) capable of deacidifying the lysosome and inhibiting autophagy significantly better than hydroxychloroquine (HCQ). Using an in situ photoaffinity pulldown strategy, we identified palmitoyl-protein thioesterase 1 (PPT1) as a molecular target shared across monomeric and dimeric CQ derivatives. HCQ and Lys05 also bound to and inhibited PPT1 activity, but only DC661 maintained activity in acidic media. Knockout of PPT1 in cancer cells using CRISPR/Cas9 editing abrogates autophagy modulation and cytotoxicity of CQ derivatives, and results in significant impairment of tumor growth similar to that observed with DC661. Elevated expression of PPT1 in tumors correlates with poor survival in patients in a variety of cancers. Thus, PPT1 represents a new target in cancer that can be inhibited with CQ derivatives.
Significance:
This study identifies PPT1 as the previously unknown lysosomal molecular target of monomeric and dimeric CQ derivatives. Genetic suppression of PPT1 impairs tumor growth, and PPT1 levels are elevated in cancer and associated with poor survival. These findings provide a strong rationale for targeting PPT1 in cancer.

This article is highlighted in the In This Issue feature, p. 151
Data from Genetic Predictors of Response to Systemic Therapy in Esophagogastric Cancer
Authors: Janjigian Yelena Y. , Sanchez-Vega Francisco , Jonsson Philip , Chatila Walid K. , Hechtman Jaclyn F. , Ku Geoffrey Y. , Riches Jamie C. , Tuvy Yaelle , Kundra Ritika , Bouvier Nancy , Vakiani Efsevia , Gao Jianjiong , Heins Zachary J. , Gross Benjamin E. , Kelsen David P. , Zhang Liying , Strong Vivian E. , Schattner Mark , Gerdes Hans , Coit Daniel G. , Bains Manjit , Stadler Zsofia K. , Rusch Valerie W. , Jones David R. , Molena Daniela , Shia Jinru , Robson Mark E. , Capanu Marinela , Middha Sumit , Zehir Ahmet , Hyman David M. , Scaltriti Maurizio , Ladanyi Marc , Rosen Neal , Ilson David H. , Berger Michael F. , Tang Laura , Taylor Barry S. , Solit David B. , Schultz Nikolaus
Published: April 2023

Abstract
The incidence of esophagogastric cancer is rapidly rising, but only a minority of patients derive durable benefit from current therapies. Chemotherapy as well as anti-HER2 and PD-1 antibodies are standard treatments. To identify predictive biomarkers of drug sensitivity and mechanisms of resistance, we implemented prospective tumor sequencing of patients with metastatic esophagogastric cancer. There was no association between homologous recombination deficiency defects and response to platinum-based chemotherapy. Patients with microsatellite instability–high tumors were intrinsically resistant to chemotherapy but more likely to achieve durable responses to immunotherapy. The single Epstein–Barr virus–positive patient achieved a durable, complete response to immunotherapy. The level of ERBB2 amplification as determined by sequencing was predictive of trastuzumab benefit. Selection for a tumor subclone lacking ERBB2 amplification, deletion of ERBB2 exon 16, and comutations in the receptor tyrosine kinase, RAS, and PI3K pathways were associated with intrinsic and/or acquired trastuzumab resistance. Prospective genomic profiling can identify patients most likely to derive durable benefit to immunotherapy and trastuzumab and guide strategies to overcome drug resistance.

Significance: Clinical application of multiplex sequencing can identify biomarkers of treatment response to contemporary systemic therapies in metastatic esophagogastric cancer. This large prospective analysis sheds light on the biological complexity and the dynamic nature of therapeutic resistance in metastatic esophagogastric cancers. Cancer Discov; 8(1); 49–58. ©2017 AACR.

See related commentary by Sundar and Tan, p. 14.

See related article by Pectasides et al., p. 37.

This article is highlighted in the In This Issue feature, p. 1