bluuebunny/crossref_metadata_2025 huggingface dataset:
Figure S4 from Radiosensitization In Vivo by Histone Deacetylase Inhibition with No Increase in Early Normal Tissue Radiation Toxicity
Authors: Groselj Blaz , Ruan Jia-Ling , Scott Helen , Gorrill Jessica , Nicholson Judith , Kelly Jacqueline , Anbalagan Selvakumar , Thompson James , Stratford Michael R.L. , Jevons Sarah J. , Hammond Ester M. , Scudamore Cheryl L. , Kerr Martin , Kiltie Anne E.
Published: April 2023

HDAC expression and cellular response to HDAC inhibition. A) qPCR of mRNA expression of HDAC 1-11 genes in normal human urothelial cells (NHU) and RT112, CAL29 and T24 bladder cancer cells. Relative gene expression was normalised to GAPDH levels (n=3); B) Effects of panobinostat on expression of selected HDAC proteins (n=2); C) Clonogenic assay representing cytotoxicity of mocetinostat in RT112, CAL29 and T24 bladder cancer cells, after 24 h incubation (n=3); D) Clonogenic assay representing cytotoxicity of TMP195 in RT112 cells, after 24 h incubation (n=3); E) Effect of panobinostat on acetylation levels of histone H3 lysine 18 (H3K18) at 0.5, 1, 2, 3 and 24 h incubation in RT112 cells (n=2); F) Quantification of western blots in Figure 6 (n=3 for MRE11, HDAC1 and NBS1, n=2 for HDAC2 and RAD51); G) HR assay results for TMP195 (n=3).
Figure S1 from Radiosensitization In Vivo by Histone Deacetylase Inhibition with No Increase in Early Normal Tissue Radiation Toxicity
Authors: Groselj Blaz , Ruan Jia-Ling , Scott Helen , Gorrill Jessica , Nicholson Judith , Kelly Jacqueline , Anbalagan Selvakumar , Thompson James , Stratford Michael R.L. , Jevons Sarah J. , Hammond Ester M. , Scudamore Cheryl L. , Kerr Martin , Kiltie Anne E.
Published: April 2023

Days for RT112 xenografts to treble in volume and body weights and treatment of Ku80KD xenografts. A) Days for xenografts to treble in volume (PAN+IR vs IR, p=0.06). Skin overlying the xenograft developed ulceration in two mice treated with IR alone and four mice in the PAN+IR group, beyond the time to treble tumour volume; B) Body weight in mice carrying RT112 xenografts, vehicle (n=5), PAN (n=7), PAN+IR (n=6) or IR alone (n=6); C) Mouse body weights in mice carrying 30% KuKD xenografts for vehicle (n=4), PAN (n=6), PAN+IR (n=6) or IR alone (n=6); D) Ku80 knock-down cells express approximately 70% protein; E) Treatment of Ku80KD xenograft mice.
Supplementary Methods, Table S1, and Figures S1-S6 from Selective and Concentrated Accretion of SN-38 with a CEACAM5-Targeting Antibody–Drug Conjugate (ADC), Labetuzumab Govitecan (IMMU-130)
Authors: Sharkey Robert M. , Govindan Serengulam V. , Cardillo Thomas M. , Donnell Jennifer , Xia Jing , Rossi Edmund A. , Chang Chien-Hsing , Goldenberg David M.
Published: April 2023

Supplementary Table S1. Extraction efficiency for isolation of SN-38 in buffer with or without human serum albumin (HSA) or from the ADC with or without acid hydrolysis followed by extraction; Supplementary Figure S1. Schematic depiction of the conjugation of CL2A-SN-38 to mildly reduced IgG yielding site-specifically coupled SN-38 to 8 well-defined sites; Supplementary Figure S2. CL2A-SN38 amide capped with N-acetylcysteine; Supplementary Figure S3. SDS-Page gels comparing profiles for labetuzumab (unconjugated hMN-14 IgG) and labetuzumab govitecan (CL2A-SN-38 conjugated hMN-14 IgG; IMMU-130); Supplementary Figure S4. In vitro cell binding assay performed on LS174T cells, evaluating the binding of unconjugated hMN-14 IgG and SN-38-conjugated hMN-14 IgG (IMMU-130); Supplementary Figure S5. Stability of IMMU-130 in serum from different sources; Supplementary Figure S6. Evaluation of lactone ring stability of the CL2A-linked SN-38 compared to SN-38 at pH 7.4.
Supplementary Figures S1-S2 and Full unedited western blots from Mechanistic Investigations of Diarrhea Toxicity Induced by Anti-HER2/3 Combination Therapy
Authors: Moisan Annie , Michielin Francesca , Jacob Wolfgang , Kronenberg Sven , Wilson Sabine , Avignon Blandine , Gérard Régine , Benmansour Fethallah , McIntyre Christine , Meneses-Lorente Georgina , Hasmann Max , Schneeweiss Andreas , Weisser Martin , Adessi Céline
Published: April 2023

1. Supplementary Figure 1. Illustration of tubes area detection as rectangles based on the bright field channel. 2. Supplementary Figure 2. Diarrhea severity during combination treatment with lumretuzumab (RO5479599), pertuzumab and paclitaxel in patients. 3. Full Unedited western blots of figures 2c and 2d
Supplementary Figures S1-S6 from The Unfolded Protein Response: A Novel Therapeutic Target for Poor Prognostic BRAF Mutant Colorectal Cancer
Authors: Forsythe Nicholas , Refaat Alaa , Javadi Arman , Khawaja Hajrah , Weir Jessica-Anne , Emam Heba , Allen Wendy L. , Burkamp Frank , Popovici Vlad , Jithesh Puthen V. , Isella Claudio , Labonte Melissa J. , Mills Ian G. , Johnston Patrick G. , Van Schaeybroeck Sandra
Published: April 2023

Figure S1: Discovery and validation datasets used in the study; Figure S2: Sensitivity of BRAFMT and WT CRC cells to acute ER stress induction; Figure S3: Sensitivity of BRAFMT and WT CRC cells to ACY-1215 and carfilzomib; Figure S4: Effect of combined ACY-1215 and carfilzomib on survival of BRAFMT and WT CRC cells; Figure S5: Effect of combined ACY-1215 and carfilzomib on accumulation of ubiquitinated proteins; Figure S6: Tolerability of combined ACY-1215/carfilzomib treatment in BALB/c nude mice
Figure S5 from Exploiting Arginine Auxotrophy with Pegylated Arginine Deiminase (ADI-PEG20) to Sensitize Pancreatic Cancer to Radiotherapy via Metabolic Dysregulation
Authors: Singh Pankaj K. , Deorukhkar Amit A. , Venkatesulu Bhanu P. , Li Xiaolin , Tailor Ramesh , Bomalaski John S. , Krishnan Sunil
Published: April 2023

Ki67 and VEGF
Supplementary Figure 6 from Neutralization of BCL-2/XL Enhances the Cytotoxicity of T-DM1 In Vivo
Authors: Zoeller Jason J. , Vagodny Aleksandr , Taneja Krishan , Tan Benjamin Y. , O'Brien Neil , Slamon Dennis J. , Sampath Deepak , Leverson Joel D. , Bronson Roderick T. , Dillon Deborah A. , Brugge Joan S.
Published: April 2023

HER2 levels post-treatment.
Supplementary Figure 3 from Neutralization of BCL-2/XL Enhances the Cytotoxicity of T-DM1 In Vivo
Authors: Zoeller Jason J. , Vagodny Aleksandr , Taneja Krishan , Tan Benjamin Y. , O'Brien Neil , Slamon Dennis J. , Sampath Deepak , Leverson Joel D. , Bronson Roderick T. , Dillon Deborah A. , Brugge Joan S.
Published: April 2023

Macroscopic comparison of tumors.
Supplementary Figure 4 from Structural and Functional Analyses of an Allosteric EYA2 Phosphatase Inhibitor That Has On-Target Effects in Human Lung Cancer Cells
Authors: Anantharajan Jothi , Zhou Hengbo , Zhang Lingdi , Hotz Taylor , Vincent Melanie Y. , Blevins Melanie A. , Jansson Anna E. , Kuan John Wee Liang , Ng Elizabeth Yihui , Yeo Yee Khoon , Baburajendran Nithya , Lin Grace , Hung Alvin W. , Joy Joma , Patnaik Samarjit , Marugan Juan , Rudra Pratyaydipta , Ghosh Debashis , Hill Jeffrey , Keller Thomas H. , Zhao Rui , Ford Heide L. , Kang CongBao
Published: April 2023

Eya2 and Six1 expression in different lung cancer cell lines, along with the effects of Eya2 and Eya2 D274N on protein localization and EMT markers.
Supplementary Figures 1 through 4 and Supplementary Table 1 from Gene Knockdown by EpCAM Aptamer–siRNA Chimeras Suppresses Epithelial Breast Cancers and Their Tumor-Initiating Cells
Authors: Gilboa-Geffen Adi , Hamar Peter , Le Minh T.N. , Wheeler Lee Adam , Trifonova Radiana , Petrocca Fabio , Wittrup Anders , Lieberman Judy
Published: April 2023

Supplemental Figure 1 shows the stability of EpCAM-AsiCs in serum. Supplemental Figure 2 shows that injection of EpCAM-AsiCs in immunocompetent mice does not trigger innate immunity. Supplemental Figure 3 shows that the siRNA within the AsiC associates with Argonaute after it is processed in cells. Supplemental Figure 4 shows that subcutaneous injection of the PLK1 EpCAM-AsiC suppresses the growth of MCF10CA1a tumors in tumor-bearing mice. Supplemental Table 1 contains EpCAM-AsiC sequences used in this paper.
Supplementary Figure S2 from Androgen Receptor Signaling Reduces Radiosensitivity in Bladder Cancer
Authors: Ide Hiroki , Inoue Satoshi , Mizushima Taichi , Jiang Guiyang , Chuang Kuang-Hsiang , Oya Mototsugu , Miyamoto Hiroshi
Published: April 2023

Expression of DNA repair genes in irradiated AR-negative bladder cancer cells.
Table S1 from Sensitization of Glioblastoma Cells to Irradiation by Modulating the Glucose Metabolism
Authors: Shen Han , Hau Eric , Joshi Swapna , Dilda Pierre J. , McDonald Kerrie L.
Published: April 2023

Table S1. The surviving fractions of GBM cell lines after treatment with DCA as a single agent.
Supplementary Data Figure S8 from CNDAC-Induced DNA Double-Strand Breaks Cause Aberrant Mitosis Prior to Cell Death
Authors: Liu Xiaojun , Jiang Yingjun , Takata Kei-ichi , Nowak Billie , Liu Chaomei , Wood Richard D. , Hittelman Walter N. , Plunkett William
Published: April 2023

Supplemental Figure S8 shows multinucleation or nuclear fragmentation revealed in AA8 cells stably expressing H2B-GFP after CNDAC washout.
Supplementary Movie S1 from Development of a RSK Inhibitor as a Novel Therapy for Triple-Negative Breast Cancer
Authors: Ludwik Katarzyna A. , Campbell J. Preston , Li Mingzong , Li Yu , Sandusky Zachary M. , Pasic Lejla , Sowder Miranda E. , Brenin David R. , Pietenpol Jennifer A. , O'Doherty George A. , Lannigan Deborah A.
Published: April 2023

Scratch assay using MDA-MB-231 cells. Top vehicle, bottom (1b) (50 μM) over a 7h time frame.
Figure S4 from Targeting AKT with Oridonin Inhibits Growth of Esophageal Squamous Cell Carcinoma In Vitro and Patient-Derived Xenografts In Vivo
Authors: Song Mengqiu , Liu Xuejiao , Liu Kangdong , Zhao Ran , Huang Hai , Shi Yuanyuan , Zhang Man , Zhou Silei , Xie Hua , Chen Hanyong , Li Yin , Zheng Yan , Wu Qiong , Liu Fangfang , Li Enmin , Bode Ann M. , Dong Zigang , Lee Mee-Hyun
Published: April 2023

Representative photographs of cell cycle after oridonin treatment in ESCC cells. Cell cycle was assessed by flow cytometry in KYSE70, KYSE410 and KYSE450 cells after treatment with different concentrations of oridonin (0, 5, 10 or 20 μM).
Supplementary Table II from Inhibition of Wild-Type p53-Expressing AML by the Novel Small Molecule HDM2 Inhibitor CGM097
Authors: Weisberg Ellen , Halilovic Ensar , Cooke Vesselina G. , Nonami Atsushi , Ren Tao , Sanda Takaomi , Simkin Irene , Yuan Jing , Antonakos Brandon , Barys Louise , Ito Moriko , Stone Richard , Galinsky Ilene , Cowens Kristen , Nelson Erik , Sattler Martin , Jeay Sebastien , Wuerthner Jens U. , McDonough Sean M. , Wiesmann Marion , Griffin James D.
Published: April 2023

Supplementary Table II: Cell lines tested with HDM2 inhibitor, CGM097: IC50 values for CGM097.
Supplementary Table 3 from Tumor-Independent Host Secretomes Induced By Angiogenesis and Immune-Checkpoint Inhibitors
Authors: Mastri Michalis , Lee Christina R. , Tracz Amanda , Kerbel Robert S. , Dolan Melissa , Shi Yuhao , Ebos John M.L.
Published: April 2023

Summary of drug doses and administration information
Supplementary Table 1 from Tumor-Independent Host Secretomes Induced By Angiogenesis and Immune-Checkpoint Inhibitors
Authors: Mastri Michalis , Lee Christina R. , Tracz Amanda , Kerbel Robert S. , Dolan Melissa , Shi Yuhao , Ebos John M.L.
Published: April 2023

List of all gene set enrichment analysis for each drug with NES, NOM-p values, and Weight Rank Score.
Supplementary Figure S6 from Expression of Genes Involved in Vascular Morphogenesis and Maturation Predicts Efficacy of Bevacizumab-Based Chemotherapy in Patients Undergoing Liver Resection
Authors: Stremitzer Stefan , Zhang Wu , Yang Dongyun , Ning Yan , Sunakawa Yu , Matsusaka Satoshi , Parekh Anish , Okazaki Satoshi , Hanna Diana , Astrow Stephanie H. , Moran Miriana , Hernandez Jose , Stephens Craig , Scherer Stefan J. , Stift Judith , Wrba Friedrich , Gruenberger Thomas , Lenz Heinz-Josef
Published: April 2023

Kaplan Meier curves for EPHB4 mRNA levels in CLM for RFS (complete response, CR)
Supplementary Figure S2 from AZD6738, A Novel Oral Inhibitor of ATR, Induces Synthetic Lethality with ATM Deficiency in Gastric Cancer Cells
Authors: Min Ahrum , Im Seock-Ah , Jang Hyemin , Kim Seongyeong , Lee Miso , Kim Debora Keunyoung , Yang Yaewon , Kim Hee-Jun , Lee Kyung-Hun , Kim Jin Won , Kim Tae-Yong , Oh Do-Youn , Brown Jeff , Lau Alan , O'Connor Mark J. , Bang Yung-Jue
Published: April 2023

Effects of AZD6738 on DNA damage repair capacity
Supplementary File from A Prodrug of Two Approved Drugs, Cisplatin and Chlorambucil, for Chemo War Against Cancer
Authors: Pathak Rakesh K. , Wen Ru , Kolishetti Nagesh , Dhar Shanta
Published: April 2023

Supplementary Materials and Methods. Figure S1. 1H NMR of Platin-Cbl using DMSO-d6; Figure S2. 13C NMR of Platin-Cbl using DMSO-d6; Figure S3. 195Pt NMR of Platin-Cbl using DMSO-d6; Figure S4. HRMS-ESI of Platin-Cbl along with observed and calculated isotopic distributions; Figure S5. Feasible reduction of Platin-Cbl at pH 7.4 and different scan rates in mV s-1 using cyclic voltammetry; Figure S6. Cytotoxicity of cisplatin, Cbl, cisplatin+2Cbl, Platin-Cbl, NT/T-Platin-Cbl-NPs in (A) 4T1 and (B) MCF-7 cells by MTT assay; Figure S7. A summary of one dose NCI-60 cell line data with Platin-Cbl; Figure S8. A summary of five dose NCI-60 cell line data with Platin-Cbl; Figure S9. A summary of one dose NCI-60 cell line data with Platin-B; Figure S10. A summary of five dose NCI-60 cell line data with Platin-B; Figure S11. Apoptosis vs. necrosis assay in A2780/CP70 cells in presence of cisplatin; Figure S12. Uptake of cisplatin, platin-Cbl, and T/NT-NPs of Platin-Cbl in A2780/CP70 cells; Figure S13. GSH levels in A2780/CP70 cells after treatment with NT/T-Platin-Cbl-NPs; Figure S14. Analysis of mitochondrial respiration in A2780/CP70 cells upon treatment with TPlatin- Cbl-NP (1, 2, 3, or 4 μM with respect to Platin-Cbl) for 24 h using Seahorse analyzer; Figure S15. (A) Analysis of mitochondrial bioenergetics in PC3 cells upon treatment with Cbl; Figure S16. (A) Analysis of mitochondrial bioenergetics in A2780 cells upon treatment with Cbl;Figure S17. Glycolysis stress assay in A2780/CP70 cells after treatment with NT/T-Platin-Cbl-NPs.
Supplementary Table S4 from Intermittent High-Dose Scheduling of AZD8835, a Novel Selective Inhibitor of PI3Kα and PI3Kδ, Demonstrates Treatment Strategies for PIK3CA-Dependent Breast Cancers
Authors: Hudson Kevin , Hancox Urs J. , Trigwell Cath , McEwen Robert , Polanska Urszula M. , Nikolaou Myria , Morentin Gutierrez Pablo , Avivar-Valderas Alvaro , Delpuech Oona , Dudley Phillippa , Hanson Lyndsey , Ellston Rebecca , Jones Alys , Cumberbatch Marie , Cosulich Sabina C. , Ward Lara , Cruzalegui Francisco , Green Stephen
Published: April 2023

Design and outcome details for each AZD8835 in vivo efficacy study.
Supplementary Table S3 from An Artificially Designed Interfering lncRNA Expressed by Oncolytic Adenovirus Competitively Consumes OncomiRs to Exert Antitumor Efficacy in Hepatocellular Carcinoma
Authors: Li Xiaoya , Su Yinghan , Sun Bin , Ji Weidan , Peng Zhangxiao , Xu Yang , Wu Mengchao , Su Changqing
Published: April 2023

Adenovirus-expressed lncRNAi affects miRNAs profiles in HCC cells
Supplementary Video legends from Combination of Eribulin and Aurora A Inhibitor MLN8237 Prevents Metastatic Colonization and Induces Cytotoxic Autophagy in Breast Cancer
Authors: Kozyreva Varvara K. , Kiseleva Anna A. , Ice Ryan J. , Jones Brandon C. , Loskutov Yuriy V. , Matalkah Fatimah , Smolkin Matthew B. , Marinak Kristina , Livengood Ryan H. , Salkeni Mohamad A. , Wen Sijin , Hazard Hannah W. , Layne Ginger P. , Walsh Callee M. , Cantrell Pamela S. , Kilby Greg W. , Mahavadi Sricharan , Shah Neal , Pugacheva Elena N.
Published: April 2023

File contains detailed information on Supplementary video files.
Supplementary Information from Ras–MEK Signaling Mediates a Critical Chk1-Dependent DNA Damage Response in Cancer Cells
Authors: Lee Ho-June , Cao Yi , Pham Victoria , Blackwood Elizabeth , Wilson Catherine , Evangelista Marie , Klijn Christiaan , Stokoe David , Settleman Jeff
Published: April 2023

Supplementary Methods Supplementary Figure S1: Gö6976 selectively inhibits osteosarcoma cell growth through Chk1 inhibition in a p53-independent manner Supplementary Figure S2: Relationship between GDC-0425 sensitivity and Chk1 expression in cell lines derived from the indicated tissue types Supplementary Figure S3: Ras-MEK signaling is associated with Chk1 dependency Supplementary Figure S4: Feedback activation of Ras-MEK by Chk1 inhibition Supplementary Figure S5: BT-549 cells were treated with either GDC-0425 or cobimetinib alone or combination for 24 hr. Supplementary Figure S6: Synergistic anti-tumor growth activity by gemcitabine/GDC-0425 combination treatment in Chk1-dependent cancer cells.
Supplementary figures S1-S3 from Antitumor and Antiangiogenic Effects of Aspirin-PC in Ovarian Cancer
Authors: Huang Yan , Lichtenberger Lenard M. , Taylor Morgan , Bottsford-Miller Justin N. , Haemmerle Monika , Wagner Michael J. , Lyons Yasmin , Pradeep Sunila , Hu Wei , Previs Rebecca A. , Hansen Jean M. , Fang Dexing , Dorniak Piotr L. , Filant Justyna , Dial Elizabeth J. , Shen Fangrong , Hatakeyama Hiroto , Sood Anil K.
Published: April 2023

Figure S-1. Chemical structures of aspirin and the predominant phospholipid in soybean phosphatidylcholine (PC).Figure S-2. Evaluation of the effects of aspirin-PC and aspirin on tube-formation. Figure S-3. In vitro evidence that the growth inhibitory activity of aspirin-PC and aspirin of ovarian cancer cell lines.
Figure S4 from Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (Ulixertinib)
Authors: Germann Ursula A. , Furey Brinley F. , Markland William , Hoover Russell R. , Aronov Alex M. , Roix Jeffrey J. , Hale Michael , Boucher Diane M. , Sorrell David A. , Martinez-Botella Gabriel , Fitzgibbon Matthew , Shapiro Paul , Wick Michael J. , Samadani Ramin , Meshaw Kathryn , Groover Anna , DeCrescenzo Gary , Namchuk Mark , Emery Caroline M. , Saha Saurabh , Welsch Dean J.
Published: April 2023

For xenograft experiments body weight (grams) are plotted over time (days) for different BVD-523 treatment groups in experiment using (A) A375 (n=15 for BVD-523 treatment groups, n= 10 for vehicle group), (B) Colo205 (n=12), (D) MIAPaCa2 (n=12), and (F) ZR-75.1 (n=15). Mean tumor volume {plus minus}SEM over time (days), is shown for (C) MIAPaCA2 and (E) ZR-75.1, following BVD-523 treatment.
Figure S1 from Synthetic Lethality Interaction Between Aurora Kinases and CHEK1 Inhibitors in Ovarian Cancer
Authors: Alcaraz-Sanabria Ana , Nieto-Jiménez Cristina , Corrales-Sánchez Verónica , Serrano-Oviedo Leticia , Andrés-Pretel Fernando , Montero Juan Carlos , Burgos Miguel , Llopis Juan , Galán-Moya Eva María , Pandiella Atanasio , Ocaña Alberto
Published: April 2023

Dose-response curves in the human keratinocyte cell line, HACAT and Synergistic effect of Alisertib, LY2603618 and chemotherapies.
Makena et al Supplemantary Tables and Figures from Reactive Oxygen Species–Mediated Synergism of Fenretinide and Romidepsin in Preclinical Models of T-cell Lymphoid Malignancies
Authors: Makena Monish R. , Koneru Balakrishna , Nguyen Thinh H. , Kang Min H. , Reynolds C. Patrick
Published: April 2023

Table of cell lines and PDXs used. Table of antibodies used Supplementary Figures 1 to 11
Figure S1 from Mutual Influence of ROS, pH, and CLIC1 Membrane Protein in the Regulation of G1–S Phase Progression in Human Glioblastoma Stem Cells
Authors: Peretti Marta , Raciti Federica Maddalena , Carlini Valentina , Verduci Ivan , Sertic Sarah , Barozzi Sara , Garré Massimiliano , Pattarozzi Alessandra , Daga Antonio , Barbieri Federica , Costa Alex , Florio Tullio , Mazzanti Michele
Published: April 2023

IAA-94 blockade induces G1 cell cycle arrest in GBM cancer stem cells.
Figure S6 from IL6 Receptor Blockade Enhances Chemotherapy Efficacy in Pancreatic Ductal Adenocarcinoma
Authors: Long Kristen B. , Tooker Graham , Tooker Evan , Luque Santiago Lombo , Lee Jae W. , Pan Xiaoqing , Beatty Gregory L.
Published: April 2023

IL-6Ralpha expression on murine PDAC cell lines
Table S2 from Novel Fluoroindenoisoquinoline Non-Camptothecin Topoisomerase I Inhibitors
Authors: Marzi Laetitia , Agama Keli , Murai Junko , Difilippantonio Simone , James Amy , Peer Cody J. , Figg William D. , Beck Daniel , Elsayed Mohamed S.A. , Cushman Mark , Pommier Yves
Published: April 2023

Correlation of LMP135 with NCI-60 drug database
Supplemental Tables 1-3 from Response and Resistance to Paradox-Breaking BRAF Inhibitor in Melanomas In Vivo and Ex Vivo
Authors: Hartsough Edward J. , Kugel Curtis H. , Vido Michael J. , Berger Adam C. , Purwin Timothy J. , Goldberg Allison , Davies Michael A. , Schiewer Matthew J. , Knudsen Karen E. , Bollag Gideon , Aplin Andrew E.
Published: April 2023

Supplemental Table 1: Patient data and treatment history Supplemental Table 2: PBRT #15 Ion Torrent results Supplemental Table 3: PBRT #16 Ion Torrent results
Figure S1 from Folate-Hapten–Mediated Immunotherapy Synergizes with Vascular Endothelial Growth Factor Receptor Inhibitors in Treating Murine Models of Cancer
Authors: Bandara N. Achini , Bates Cody D. , Lu Yingjuan , Hoylman Emily K. , Low Philip S.
Published: April 2023

Anti-FITC antibody titers determined for mice immunized with KLH-FITC plus GPI-0100. Blood collected from immunized mice was pooled for different treatment groups prior to titer analysis, while blood collected from non-immunized mice was pooled and used as a control (open circles).
Supplementary Figure 5 from Altered Steroid Milieu in AI-Resistant Breast Cancer Facilitates AR Mediated Gene-Expression Associated with Poor Response to Therapy
Authors: Creevey Laura , Bleach Rachel , Madden Stephen F. , Toomey Sinead , Bane Fiona T. , Varešlija Damir , Hill Arnold D. , Young Leonie S. , McIlroy Marie
Published: April 2023

Impact of SiSGK3 in ZRaroLetR. MTS following siSGK3 under various hormonal stimuli.
Figure S2 from Arsenic Trioxide and Sorafenib Induce Synthetic Lethality of FLT3-ITD Acute Myeloid Leukemia Cells
Authors: Wang Rui , Li Ying , Gong Ping , Gabrilove Janice , Waxman Samuel , Jing Yongkui
Published: April 2023

The effect of AC220 on GSK3beta phosphorylation and ATO-induced apoptosis.
Supplementary Figure S6 from Functional Analysis of Somatic Mutations Affecting Receptor Tyrosine Kinase Family in Metastatic Colorectal Cancer
Authors: Duplaquet Leslie , Figeac Martin , Leprêtre Frédéric , Frandemiche Charline , Villenet Céline , Sebda Shéhérazade , Sarafan-Vasseur Nasrin , Bénozène Mélanie , Vinchent Audrey , Goormachtigh Gautier , Wicquart Laurence , Rousseau Nathalie , Beaussire Ludivine , Truant Stéphanie , Michel Pierre , Sabourin Jean-Christophe , Galateau-Sallé Françoise , Copin Marie-Christine , Zalcman Gérard , De Launoit Yvan , Fafeur Véronique , Tulasne David
Published: April 2023

Supplementary Figure S6: Amino acid sequence alignment of the VEGFR1 and VEGFR3 kinase domains
Supplementary Figure S2 from Functional Analysis of Somatic Mutations Affecting Receptor Tyrosine Kinase Family in Metastatic Colorectal Cancer
Authors: Duplaquet Leslie , Figeac Martin , Leprêtre Frédéric , Frandemiche Charline , Villenet Céline , Sebda Shéhérazade , Sarafan-Vasseur Nasrin , Bénozène Mélanie , Vinchent Audrey , Goormachtigh Gautier , Wicquart Laurence , Rousseau Nathalie , Beaussire Ludivine , Truant Stéphanie , Michel Pierre , Sabourin Jean-Christophe , Galateau-Sallé Françoise , Copin Marie-Christine , Zalcman Gérard , De Launoit Yvan , Fafeur Véronique , Tulasne David
Published: April 2023

Supplementary Figure S2: Validation of 9 somatic mutations in RTKs by Sanger sequencing
Supplementary Figure S1 from Functional Analysis of Somatic Mutations Affecting Receptor Tyrosine Kinase Family in Metastatic Colorectal Cancer
Authors: Duplaquet Leslie , Figeac Martin , Leprêtre Frédéric , Frandemiche Charline , Villenet Céline , Sebda Shéhérazade , Sarafan-Vasseur Nasrin , Bénozène Mélanie , Vinchent Audrey , Goormachtigh Gautier , Wicquart Laurence , Rousseau Nathalie , Beaussire Ludivine , Truant Stéphanie , Michel Pierre , Sabourin Jean-Christophe , Galateau-Sallé Françoise , Copin Marie-Christine , Zalcman Gérard , De Launoit Yvan , Fafeur Véronique , Tulasne David
Published: April 2023

Supplementary Figure S1: KRAS somatic mutations detected by NGS and diagnosis and number of somatic mutations affecting each RTK
Figure S2 from A Novel Theranostic Strategy for MMP-14–Expressing Glioblastomas Impacts Survival
Authors: Mohanty Suchismita , Chen Zixin , Li Kai , Morais Goreti Ribeiro , Klockow Jessica , Yerneni Ketan , Pisani Laura , Chin Frederick T. , Mitra Siddharta , Cheshier Samuel , Chang Edwin , Gambhir Sanjiv Sam , Rao Jianghong , Loadman Paul M. , Falconer Robert A. , Daldrup-Link Heike E.
Published: April 2023

Flowcytometric characterization of GICs in pcGBM39 and pcGBM2
Figure S5 from The Rolipram–Perillyl Alcohol Conjugate (NEO214) Is A Mediator of Cell Death through the Death Receptor Pathway
Authors: Cho Hee-Yeon , Thein Thu Zan , Wang Weijun , Swenson Stephen D. , Fayngor Rochelle A. , Ou Mengting , Marín-Ramos Nagore I. , Schönthal Axel H. , Hofman Florence M. , Chen Thomas C.
Published: April 2023

Acute and Chronic toxicity of NEO214.
Supplementary Figure S5 from Glibenclamide Targets Sulfonylurea Receptor 1 to Inhibit p70S6K Activity and Upregulate KLF4 Expression to Suppress Non-Small Cell Lung Carcinoma
Authors: Xu Kexin , Sun Geng , Li Min , Chen Hongling , Zhang Zuhao , Qian Xixi , Li Ping , Xu Lin , Huang Wenbin , Wang Xuerong
Published: April 2023

Supplementary Figure S5 shows the proteomics analysis of p70S6K binding proteins in HEK293T cells.
Supplementary Fig. S2 from TAS4464, A Highly Potent and Selective Inhibitor of NEDD8-Activating Enzyme, Suppresses Neddylation and Shows Antitumor Activity in Diverse Cancer Models
Authors: Yoshimura Chihoko , Muraoka Hiromi , Ochiiwa Hiroaki , Tsuji Shingo , Hashimoto Akihiro , Kazuno Hiromi , Nakagawa Fumio , Komiya Yu , Suzuki Satoshi , Takenaka Toru , Kumazaki Masafumi , Fujita Naoya , Mizutani Takashi , Ohkubo Shuichi
Published: April 2023

Supplementary Figure S2. NAE inhibitory effects of TAS4464. (A) E1 inhibitory effects of TAS4464 on HCT116 cells. Cells were treated with TAS4464 for 1 h. (B) Competition assay with non-labeled TAS4464. HCT116 cells were pre-treated with non-labeled TAS4464 (10, 100, 1000, 10000 nmol/L) and treated with 100 nmol/L 14C TAS4464 for 4 hours. (C) Dual-color detection of NEDD8 and UBC12. CCRF-CEM cells were treated with 100 nmol/L of TAS4464 for 1 to 24 h.
Supplementary Figure 2 from Precision Chemoradiotherapy for HER2 Tumors Using Antibody Conjugates of an Auristatin Derivative with Reduced Cell Permeability
Authors: Hingorani Dina V. , Doan Matthew K. , Camargo Maria F. , Aguilera Joseph , Song Seung M. , Pizzo Donald , Scanderbeg Daniel J. , Cohen Ezra E.W. , Lowy Andrew M. , Adams Stephen R. , Advani Sunil J.
Published: April 2023

Cell line HER2 expression and Anti-HER2 antibody drug conjugate binding.
Supplementary Fig S4 from TAS-121, A Selective Mutant EGFR Inhibitor, Shows Activity Against Tumors Expressing Various EGFR Mutations Including T790M and Uncommon Mutations G719X
Authors: Ito Kimihiro , Nishio Makoto , Kato Masanori , Murakami Haruyasu , Aoyagi Yoshimi , Ohe Yuichiro , Okayama Takashige , Hashimoto Akihiro , Ohsawa Hirokazu , Tanaka Gotaro , Nonoshita Katsumasa , Ito Satoru , Matsuo Kenichi , Miyadera Kazutaka
Published: April 2023

Supplementary Fig. S4 shows dose-dependency of Cmax (A) and AUC0-24h (B) in nude mice.
Supplementary Tables from Therapeutic Inhibition of the Receptor Tyrosine Kinase AXL Improves Sensitivity to Platinum and Taxane in Ovarian Cancer
Authors: Quinn Jeanne M. , Greenwade Molly M. , Palisoul Marguerite L. , Opara Gregory , Massad Katina , Guo Lei , Zhao Peinan , Beck-Noia Hollie , Hagemann Ian S. , Hagemann Andrea R. , McCourt Carolyn K. , Thaker Premal H. , Powell Matthew A. , Mutch David G. , Fuh Katherine C.
Published: April 2023

Supplementary Tables. S1 - AXL expression and chemoresponse. AXL h-score is significantly higher in chemoresistant tumors. S2 - MVA to predict chemoresistance. High AXL staining is associated with chemoresistance. S3 - Clinical and Pathological Characteristics of Patient Derived OvCa.
Table S1 from RAC1b Overexpression Confers Resistance to Chemotherapy Treatment in Colorectal Cancer
Authors: Goka Erik T. , Chaturvedi Pallavi , Lopez Dayrelis T. Mesa , Garza Adriana De La , Lippman Marc E.
Published: April 2023

Table S1 Shows Rac1 Immunohistochemistry scores for normal colon and colon cancer by stage
Table S1, Table S2, Table S3, Table S4, Figure S1Figure S2, Figure S3, Figure S4, Figure S5, Figure S6, Figure S7 from Efficacy of the Antibody–Drug Conjugate W0101 in Preclinical Models of IGF-1 Receptor Overexpressing Solid Tumors
Authors: Akla Barbara , Broussas Matthieu , Loukili Noureddine , Robert Alain , Beau-Larvor Charlotte , Malissard Martine , Boute Nicolas , Champion Thierry , Haeuw Jean-Francois , Beck Alain , Perez Michel , Dreyfus Cyrille , Pavlyuk Mariya , Chetaille Eric , Corvaia Nathalie
Published: April 2023

Table S1 shows expression of IGF1R on human tissues Table S2 shows expression of IGF1R on Tumor and Normal cells Table S3 shows DAR calculation Table S4 shows impact of W0101 on cell cycle Figure S1 shows the flowchart for selection of m208F2 Figure S2 shows kinetics of internalization of murine anti-IGF1R antibodies Figure S3 shows inhibition of binding and phosphorylation of IGF-1R Figure S4 shows binding and internalisation of W0101 on MCF7 cells Figure S5 shows impact of W0101 on apoptose compared to MMAE and isotype control ADC Figure S6 shows in vivo activity of naked antibody on MCF7 and NCI-H2122 models Figure S7 demonstrated the absence of bystander effect of W0101
Supplementary Figure S2 from Ubiquitinated PCNA Drives USP1 Synthetic Lethality in Cancer
Authors: Simoneau Antoine , Engel Justin L. , Bandi Madhavi , Lazarides Katherine , Liu Shangtao , Meier Samuel R. , Choi Ashley H. , Zhang Hongxiang , Shen Binzhang , Martires Lauren , Gotur Deepali , Pham Truc V. , Li Fang , Gu Lina , Gong Shanzhong , Zhang Minjie , Wilker Erik , Pan Xuewen , Whittington Douglas A. , Throner Scott , Maxwell John P. , Chen Yingnan , Yu Yi , Huang Alan , Andersen Jannik N. , Feng Tianshu
Published: April 2023

I-138 activity in BRCA1/2 WT and mutant cells - related to Figure 2
Data from SGN-CD228A Is an Investigational CD228-Directed Antibody–Drug Conjugate with Potent Antitumor Activity across a Wide Spectrum of Preclinical Solid Tumor Models
Authors: Mazahreh Rebecca , Mason Marsha L. , Gosink John J. , Olson Devra J. , Thurman Robert , Hale Christopher , Westendorf Lori , Pires Thomas A. , Leiske Christopher I. , Carlson Markus , Nguyen Liem T. , Cochran Julia H. , Okeley Nicole M. , Yumul Roma , Jin Steven , Stone Ivan J. , Sahetya Disha , Nesterova Albina , Allred Sean , Hensley Kelly M. , Hu Rachael , Lawrence Robert , Lewis Timothy S. , Sandall Sharsti
Published: April 2023

Abstract
SGN-CD228A is an investigational antibody–drug conjugate (ADC) directed to melanotransferrin (CD228, MELTF, MFI2, p97), a cell-surface protein first identified in melanoma. SGN-CD228A consists of a humanized antibody, hL49, with high specificity and affinity for CD228 that is stably conjugated to 8 molecules of the clinically validated microtubule-disrupting agent monomethyl auristatin E (MMAE) via a novel glucuronide linker. We performed comprehensive IHC studies, which corroborated published RNA sequencing data and confirmed low CD228 expression in normal tissues and high expression in several cancers, including melanoma, squamous non–small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), colorectal cancer, and pancreatic cancer. SGN-CD228A was efficiently internalized in various tumor cell types, and its cytotoxic activity was dependent on CD228 expression and internalization and intrinsic sensitivity to the MMAE payload. Compared with the valine-citrulline dipeptide linker, the novel glucuronide linker increased the cellular retention of MMAE in vitro and conferred improved antitumor activity against melanoma cell lines in vitro and in vivo. In addition, SGN-CD228A was active across melanoma, TNBC, and NSCLC cell line- and patient-derived xenograft models with heterogeneous antigen expression. In vivo, CD228 expression was important for response to SGN-CD228A but was not well correlated across all tumor types, suggesting that other factors associated with ADC activity are important. Overall, SGN-CD228A is a CD228-directed, investigational ADC that employs innovative technology and has compelling preclinical antitumor activity. SGN-CD228A is investigated in a Phase I clinical trial (NCT04042480) in patients with advanced solid tumors.
Data from Resistance Mechanism against Trastuzumab in HER2-Positive Cancer Cells and Its Negation by Src Inhibition
Authors: Jin Mei Hua , Nam Ah-Rong , Park Ji Eun , Bang Ju-Hee , Bang Yung-Jue , Oh Do-Youn
Published: April 2023

Abstract
Trastuzumab in combination with chemotherapy is the standard of care for patients with human epidermal growth factor receptor 2 (HER2)-positive breast and gastric cancers. Several resistance mechanisms against anti-HER2 therapy have been proposed. Src activation has been suggested to be responsible for the resistance of HER2-positive breast cancer. In our study, we generated four trastuzumab-resistant (HR) cancer cell lines from HER2-amplified gastric and biliary tract cancer cell lines (SNU-216, NCI-N87, SNU-2670, and SNU-2773). Elevated Src phosphorylation was detected in SNU2670HR and NCI-N87HR cell lines, but not in SNU216HR or SNU2773HR cell lines. In SNU216HR and SNU2773HR cell lines, phospho-FAK (focal adhesion kinase) was elevated. Bosutinib as a Src inhibitor suppressed growth, cell-cycle progression, and migration in both parental and HR cell lines. Specifically, Src interacted with FAK to affect downstream molecules such as AKT, ERK, and STAT3. Bosutinib showed more potent antitumor effects in Src-activated HR cell lines than parental cell lines. Taken together, this study suggests that Src inhibition may be an effective measure to overcome trastuzumab resistance in HER2-positive cancer. Mol Cancer Ther; 16(6); 1145–54. ©2017 AACR.
Data from The XPO1 Inhibitor Selinexor Inhibits Translation and Enhances the Radiosensitivity of Glioblastoma Cells Grown In Vitro and In Vivo
Authors: Wahba Amy , Rath Barbara H. , O'Neill John W. , Camphausen Kevin , Tofilon Philip J.
Published: April 2023

Abstract
Analysis of the radiation-induced translatome of glioblastoma stem-like cells (GSC) identified an interacting network in which XPO1 serves as a major hub protein. To determine whether this nuclear export protein provides a target for radiosensitization, we defined the effects of clinically relevant XPO1 inhibitor selinexor on the radiosensitivity of glioblastoma cells. As determined by clonogenic survival analysis, selinexor enhanced the radiosensitivity of GSCs but not normal fibroblast cell lines. On the basis of γH2AX foci and neutral comet analyses, selinexor inhibited the repair of radiation-induced DNA double-strand breaks in GSCs, suggesting that the selinexor-induced radiosensitization is mediated by an inhibition of DNA repair. Consistent with a role for XPO1 in the nuclear to cytoplasm export of rRNA, selinexor reduced 5S and 18S rRNA nuclear export in GSCs, which was accompanied by a decrease in gene translation efficiency, as determined from polysome profiles, as well as in protein synthesis. In contrast, rRNA nuclear export and protein synthesis were not reduced in normal cells treated with selinexor. Orthotopic xenografts initiated from a GSC line were then used to define the in vivo response to selinexor and radiation. Treatment of mice bearing orthotopic xenografts with selinexor decreased tumor translational efficiency as determined from polysome profiles. Although selinexor treatment alone had no effect on the survival of mice with brain tumors, it significantly enhanced the radiation-induced prolongation of survival. These results indicate that selinexor enhances the radiosensitivity of glioblastoma cells and suggest that this effect involves the global inhibition of gene translation. Mol Cancer Ther; 17(8); 1717–26. ©2018 AACR.
Data from iRGD-guided Tumor-penetrating Nanocomplexes for Therapeutic siRNA Delivery to Pancreatic Cancer
Authors: Lo Justin H. , Hao Liangliang , Muzumdar Mandar D. , Raghavan Srivatsan , Kwon Ester J. , Pulver Emilia M. , Hsu Felicia , Aguirre Andrew J. , Wolpin Brian M. , Fuchs Charles S. , Hahn William C. , Jacks Tyler , Bhatia Sangeeta N.
Published: April 2023

Abstract
Pancreatic cancer is one of the leading causes of cancer-related death, with 5-year survival of 8.5%. The lack of significant progress in improving therapy reflects our inability to overcome the desmoplastic stromal barrier in pancreatic ductal adenocarcinoma (PDAC) as well as a paucity of new approaches targeting its genetic underpinnings. RNA interference holds promise in targeting key mutations driving PDAC; however, a nucleic acid delivery vehicle that homes to PDAC and breaches the stroma does not yet exist. Noting that the cyclic peptide iRGD mediates tumor targeting and penetration through interactions with αvβ3/5 integrins and neuropilin-1, we hypothesized that “tandem” peptides combining a cell-penetrating peptide and iRGD can encapsulate siRNA to form tumor-penetrating nanocomplexes (TPN) capable of delivering siRNA to PDAC. The use of directly conjugated iRGD is justified by receptor expression patterns in human PDAC biopsies. In this work, we optimize iRGD TPNs with polyethylene glycol (PEG)-peptide conjugates for systemic delivery to sites of disease. We show that TPNs effectively knockdown siRNA targets in PDAC cell lines and in an immunocompetent genetically engineered mouse model of PDAC. Furthermore, we validate their tumor-penetrating ability in three-dimensional organoids and autochthonous tumors. In murine therapeutic trials, TPNs delivering anti-Kras siRNA significantly delay tumor growth. Thus, iRGD TPNs hold promise in treating PDAC by not only overcoming physical barriers to therapy, but by leveraging the stroma to achieve knockdown of the gold-standard genetic target. Moreover, the modular construction of this delivery platform allows for facile adaptation to future genetic target candidates in pancreatic cancer. Mol Cancer Ther; 17(11); 2377–88. ©2018 AACR.
Abstract 1011: Hsa_circ_0116796 as a novel biomarker for predicting prognosis of human hepatocellular carcinoma
Authors: Do Huiwon , Kim Gyeonghwa , Lee Yu Rim , Tak Won Young , Park Soo Young , Hur Keun
Published: April 2023

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. It lacks sufficient diagnostic and prognostic markers, which leads to a poor prognosis. The survival rate of HCC patients is still low due to its highly metastatic nature. According to recent studies, non-coding RNAs play a vital role in cancer pathogenesis and may be a new diagnostic target for HCC. Circular RNA (circRNA) is a type of non-coding RNA with a closed loop structure formed by mRNA back-splicing. Its functions are miRNA sponging, translating to proteins and gene regulation. Recently, it has been found that circRNAs play a potential role at angiogenesis, metastasis, and drug resistance in many types of cancers. Thus, we aim to investigate the clinical relevance of hsa_circ_0116796 in HCC.Total RNAs from 100 pairs of HCC and corresponding normal liver (NL) tissues with different stages were extracted using QIAzol. CircRNA primers were coded including the gap junction for specificity. The expression levels were determined by quantitative real-time PCR (qRT-PCR), and its expression was normalized with GAPDH. In addition, we analyzed the correlation between hsa_circ_0116796 expression and various clinicopathological features of HCC patients. The target miRNAs were predicted in silico analyses. We found that hsa_circ_0116796 was significantly decreased in HCC tumor tissues compared to corresponding NL tissues (P<0.001). Suppression of hsa_circ_0116796 expression was associated with HCC progression (P<0.001). Moreover, hsa_circ_0116796 expression was significantly associated with T-stage (P=0.009), TNM stage (P=0.005), BCLC stage (P=0.0132), and survival (P<0.001). We provided the novel evidence for usefulness of hsa_circ_0116796 expressions as strong potential biomarkers for diagnosis and predicting prognosis of HCC patients.

Citation Format: Huiwon Do, Gyeonghwa Kim, Yu Rim Lee, Won Young Tak, Soo Young Park, Keun Hur. Hsa_circ_0116796 as a novel biomarker for predicting prognosis of human hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1011.
Abstract 1047: Plasma KRAS mutations as predictive biomarkers for pancreatic cancer in high-risk group
Authors: Cervena Klara
Published: April 2023

Pancreatic cancer (PANC) has among solid malignancies one of the lowest 5-years survival rates - less than 10%. To improve the prognosis of PANC, it is necessary to develop tools that will enable earlier diagnosis. More than 90% of PANC cases are characterized by the presence of KRAS mutations in tumor tissue that play a critical role in the initiation of PANC. Recently, attention has been focused on liquid biopsy which can better reflect the whole genetic profile of the tumor and may enable early diagnosis.

Our study aims to discover whether KRAS gene mutations can be detected in the plasma isolated from the PANC risk group patients - diabetes mellitus II (DMII) and chronic pancreatitis (CP). The KRAS mutations were analyzed in 34 PANC, 89 DMII, and 31 CP patients by droplet digital PCR. Plasma cell-free DNA was investigated for three mutations hotspots: KRAS p.G12D c.35G>A, p.G12V c.35G>T, p.G12R. Detailed results of the study are currently under evaluation and will be presented during the meeting. We believe that these results discover whether plasma analysis of KRAS mutation can serve as a biomarker for early diagnosis of malignant transformation in risk group patients.

Supported by grant AZV NU-21-07-00247, by Czech science Foundation 22-05942S and by the project National Institute for Cancer Research (Programme EXCELES, ID Project No. LX22NPO5102).

Citation Format: Klara Cervena. Plasma KRAS mutations as predictive biomarkers for pancreatic cancer in high-risk group [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1047.
Abstract 1048: Enabling higher sensitivity liquid biopsies with multiplex digital PCR NSCLC-relevant drug resistance panels
Authors: Granitsiotis Michael , Gutierrez Kimberly , Wang Youxiang , Li Jialuo , Yang Zhijie
Published: April 2023

Cancers, for example, non-small cell lung cancer (NSCLC) and colorectal cancer, are frequently associated with specific genetic mutations that serving as biomarkers to guide more specific treatments (targeted therapy). The most frequently mutated genes include EGFR, KRAS, NRAS, BRAF, HER2, PIK3CA, MET, etc. Unfortunately, screening and monitoring the most common cancer related mutations and identifying the breadth of the most common drug-resistant mutations in MRD monitoring has previously required NGS - but cost, and time for execution, limits testing frequency. Furthermore, sensitivity is typically 1-5% VAF, thus limiting early detection. While digital PCR (dPCR) can be run at a fraction of the cost, and with higher sensitivity (VAFs of 0.1 to 0.01%), due to the lack of high level of multiplexing, it was historically impractical for routine screening. Here, we show that the use 6-color naica® system (Stilla Technologies), incorporating a series of high multiplex panels developed by Atila BioSystems, is able to group and efficiently detect the most frequently druggable mutations in a single reaction within three hours. Furthermore, we are demonstrating the coverage, precision, and sensitivity necessary to make high-plex digital PCR a viable option for future liquid biopsy testing.

Citation Format: Michael Granitsiotis, Kimberly Gutierrez, Youxiang Wang, Jialuo Li, Zhijie Yang. Enabling higher sensitivity liquid biopsies with multiplex digital PCR NSCLC-relevant drug resistance panels [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1048.
Abstract 1075: Identification of resistance mechanisms to direct KRAS inhibition in pancreatic cancer
Authors: Waters Andrew Michael , Chang Wen-Hsuan , Stalnecker Clint , Edwards Cole , Yang Runying , Goodwin Craig M. , Cox Adrienne D. , Der Channing J.
Published: April 2023

KRAS mutations occur in 95% of pancreatic ductal adenocarcinomas (PDAC) and are a well-validated driver of PDAC growth. Therefore, anti-KRAS therapies are expected to make a significant impact on the treatment of this deadly cancer, where there are currently no effective targeted therapies. Supporting this premise, early clinical trial results with KRASG12C inhibitors have shown promising disease control rates (84-100%) in KRASG12C-mutant PDAC. Despite these observations, two key issues limit the impact of KRASG12C inhibitors in PDAC. First, KRASG12C(OFF) mutations comprise less than 2% of KRAS mutations in PDAC. Second, patients initially responsive to KRASG12C inhibitors invariably relapse due to treatment-induced resistance. To begin qualifying KRAS inhibitors that target KRAS mutations more frequently found in PDAC, we characterized a RAS inhibitor that targets the multiple KRAS mutations as well as wild-type RAS proteins. We evaluated the impact of this inhibitor on RAS signaling and anti-proliferative activity in KRAS-mutant pancreatic cancer human cell lines and in a panel of RASless MEFs (ras-null mouse embryo fibroblasts) stably expressing exogenous RAS mutant proteins that are commonly found in PDAC. To identify genetic mechanisms of resistance to KRAS inhibition in pancreatic cancer, we applied CRISPR-Cas9 loss-of-function screens to KRASG12C-, KRASG12D-, KRASG12R-, and KRASQ61H-mutant PDAC cells treated with KRAS inhibitors to identify genes that modulate KRAS inhibitor anti-proliferative activity. We identified expected and novel mechanisms of resistance, including those that have been observed in patients treated with KRASG12C inhibitors.

Citation Format: Andrew Michael Waters, Wen-Hsuan Chang, Clint Stalnecker, Cole Edwards, Runying Yang, Craig M. Goodwin, Adrienne D. Cox, Channing J. Der. Identification of resistance mechanisms to direct KRAS inhibition in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1075.