bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Data Figure S11 from Loss-of-Function but Not Gain-of-Function Properties of Mutant TP53 Are Critical for the Proliferation, Survival, and Metastasis of a Broad Range of Cancer Cells
Authors: Wang Zilu , Burigotto Matteo , Ghetti Sabrina , Vaillant François , Tan Tao , Capaldo Bianca D. , Palmieri Michelle , Hirokawa Yumiko , Tai Lin , Simpson Daniel S. , Chang Catherine , Huang Allan Shuai , Lieschke Elizabeth , Diepstraten Sarah T. , Kaloni Deeksha , Riffkin Chris , Huang David C.S. , Li Wai Suen Connie S.N. , Garnham Alexandra L. , Gibbs Peter , Visvader Jane E. , Sieber Oliver M. , Herold Marco J. , Fava Luca L. , Kelly Gemma L. , Strasser Andreas
Published: February 2024

Supplementary Figure S11 showing that removal of mutant TP53 does not cause a competitive growth disadvantage in diverse human cancer cell lines in culture
Supplemental Text from Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia
Authors: Varkaris Andreas , Pazolli Ermira , Gunaydin Hakan , Wang Qi , Pierce Levi , Boezio Alessandro A. , Bulku Artemisa , DiPietro Lucian , Fridrich Cary , Frost Adam , Giordanetto Fabrizio , Hamilton Erika P. , Harris Katherine , Holliday Michael , Hunter Tamieka L. , Iskandar Amanda , Ji Yongli , Larivée Alexandre , LaRochelle Jonathan R. , Lescarbeau André , Llambi Fabien , Lormil Brenda , Mader Mary M. , Mar Brenton G. , Martin Iain , McLean Thomas H. , Michelsen Klaus , Pechersky Yakov , Puente-Poushnejad Erika , Raynor Kevin , Rogala Dipali , Samadani Ramin , Schram Alison M. , Shortsleeves Kelley , Swaminathan Sweta , Tajmir Shahein , Tan Gege , Tang Yong , Valverde Roberto , Wehrenberg Bryan , Wilbur Jeremy , Williams Bret R. , Zeng Hongtao , Zhang Hanmo , Walters W. Patrick , Wolf Beni B. , Shaw David E. , Bergstrom Donald A. , Watters James , Fraser James S. , Fortin Pascal D. , Kipp D. Randal
Published: February 2024

Synthesis of mutant-selective allosteric PI3Kα inhibitors
Figure S4 from Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia
Authors: Varkaris Andreas , Pazolli Ermira , Gunaydin Hakan , Wang Qi , Pierce Levi , Boezio Alessandro A. , Bulku Artemisa , DiPietro Lucian , Fridrich Cary , Frost Adam , Giordanetto Fabrizio , Hamilton Erika P. , Harris Katherine , Holliday Michael , Hunter Tamieka L. , Iskandar Amanda , Ji Yongli , Larivée Alexandre , LaRochelle Jonathan R. , Lescarbeau André , Llambi Fabien , Lormil Brenda , Mader Mary M. , Mar Brenton G. , Martin Iain , McLean Thomas H. , Michelsen Klaus , Pechersky Yakov , Puente-Poushnejad Erika , Raynor Kevin , Rogala Dipali , Samadani Ramin , Schram Alison M. , Shortsleeves Kelley , Swaminathan Sweta , Tajmir Shahein , Tan Gege , Tang Yong , Valverde Roberto , Wehrenberg Bryan , Wilbur Jeremy , Williams Bret R. , Zeng Hongtao , Zhang Hanmo , Walters W. Patrick , Wolf Beni B. , Shaw David E. , Bergstrom Donald A. , Watters James , Fraser James S. , Fortin Pascal D. , Kipp D. Randal
Published: February 2024

Binding kinetics and potency of [1] towards tailless PI3Kα
Figure S2 from Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia
Authors: Varkaris Andreas , Pazolli Ermira , Gunaydin Hakan , Wang Qi , Pierce Levi , Boezio Alessandro A. , Bulku Artemisa , DiPietro Lucian , Fridrich Cary , Frost Adam , Giordanetto Fabrizio , Hamilton Erika P. , Harris Katherine , Holliday Michael , Hunter Tamieka L. , Iskandar Amanda , Ji Yongli , Larivée Alexandre , LaRochelle Jonathan R. , Lescarbeau André , Llambi Fabien , Lormil Brenda , Mader Mary M. , Mar Brenton G. , Martin Iain , McLean Thomas H. , Michelsen Klaus , Pechersky Yakov , Puente-Poushnejad Erika , Raynor Kevin , Rogala Dipali , Samadani Ramin , Schram Alison M. , Shortsleeves Kelley , Swaminathan Sweta , Tajmir Shahein , Tan Gege , Tang Yong , Valverde Roberto , Wehrenberg Bryan , Wilbur Jeremy , Williams Bret R. , Zeng Hongtao , Zhang Hanmo , Walters W. Patrick , Wolf Beni B. , Shaw David E. , Bergstrom Donald A. , Watters James , Fraser James S. , Fortin Pascal D. , Kipp D. Randal
Published: February 2024

PI3Kα KD Simulations
Figure S1 from Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia
Authors: Varkaris Andreas , Pazolli Ermira , Gunaydin Hakan , Wang Qi , Pierce Levi , Boezio Alessandro A. , Bulku Artemisa , DiPietro Lucian , Fridrich Cary , Frost Adam , Giordanetto Fabrizio , Hamilton Erika P. , Harris Katherine , Holliday Michael , Hunter Tamieka L. , Iskandar Amanda , Ji Yongli , Larivée Alexandre , LaRochelle Jonathan R. , Lescarbeau André , Llambi Fabien , Lormil Brenda , Mader Mary M. , Mar Brenton G. , Martin Iain , McLean Thomas H. , Michelsen Klaus , Pechersky Yakov , Puente-Poushnejad Erika , Raynor Kevin , Rogala Dipali , Samadani Ramin , Schram Alison M. , Shortsleeves Kelley , Swaminathan Sweta , Tajmir Shahein , Tan Gege , Tang Yong , Valverde Roberto , Wehrenberg Bryan , Wilbur Jeremy , Williams Bret R. , Zeng Hongtao , Zhang Hanmo , Walters W. Patrick , Wolf Beni B. , Shaw David E. , Bergstrom Donald A. , Watters James , Fraser James S. , Fortin Pascal D. , Kipp D. Randal
Published: February 2024

Activation loop residues 937-954 are more disordered in mutant vs. wildtype PI3Kα
Supplementary Table 5 from Alveolar Differentiation Drives Resistance to KRAS Inhibition in Lung Adenocarcinoma
Authors: Li Zhuxuan , Zhuang Xueqian , Pan Chun-Hao , Yan Yan , Thummalapalli Rohit , Hallin Jill , Torborg Stefan , Singhal Anupriya , Chang Jason C. , Manchado Eusebio , Dow Lukas E. , Yaeger Rona , Christensen James G. , Lowe Scott W. , Rudin Charles M. , Joost Simon , Tammela Tuomas
Published: February 2024

Supplementary Table 5 shows the primers used in this study.
Supplementary Table 1 from Alveolar Differentiation Drives Resistance to KRAS Inhibition in Lung Adenocarcinoma
Authors: Li Zhuxuan , Zhuang Xueqian , Pan Chun-Hao , Yan Yan , Thummalapalli Rohit , Hallin Jill , Torborg Stefan , Singhal Anupriya , Chang Jason C. , Manchado Eusebio , Dow Lukas E. , Yaeger Rona , Christensen James G. , Lowe Scott W. , Rudin Charles M. , Joost Simon , Tammela Tuomas
Published: February 2024

Supplementary Table 1 shows the differential gene expression analysis of autochthonous KP LUAD cells expressing shRenilla or shKras.
Supplementary Figures from Alveolar Differentiation Drives Resistance to KRAS Inhibition in Lung Adenocarcinoma
Authors: Li Zhuxuan , Zhuang Xueqian , Pan Chun-Hao , Yan Yan , Thummalapalli Rohit , Hallin Jill , Torborg Stefan , Singhal Anupriya , Chang Jason C. , Manchado Eusebio , Dow Lukas E. , Yaeger Rona , Christensen James G. , Lowe Scott W. , Rudin Charles M. , Joost Simon , Tammela Tuomas
Published: February 2024

It includes 7 supplementary figures for the paper
Supplementary Figure 8 from NKG2A Is a Therapeutic Vulnerability in Immunotherapy Resistant MHC-I Heterogeneous Triple-Negative Breast Cancer
Authors: Taylor Brandie C. , Sun Xiaopeng , Gonzalez-Ericsson Paula I. , Sanchez Violeta , Sanders Melinda E. , Wescott Elizabeth C. , Opalenik Susan R. , Hanna Ann , Chou Shu-Ting , Van Kaer Luc , Gomez Henry , Isaacs Claudine , Ballinger Tarah J. , Santa-Maria Cesar A. , Shah Payal D. , Dees Elizabeth C. , Lehmann Brian D. , Abramson Vandana G. , Pietenpol Jennifer A. , Balko Justin M.
Published: February 2024

Flow gating strategies
Supplementary Figure 6 from NKG2A Is a Therapeutic Vulnerability in Immunotherapy Resistant MHC-I Heterogeneous Triple-Negative Breast Cancer
Authors: Taylor Brandie C. , Sun Xiaopeng , Gonzalez-Ericsson Paula I. , Sanchez Violeta , Sanders Melinda E. , Wescott Elizabeth C. , Opalenik Susan R. , Hanna Ann , Chou Shu-Ting , Van Kaer Luc , Gomez Henry , Isaacs Claudine , Ballinger Tarah J. , Santa-Maria Cesar A. , Shah Payal D. , Dees Elizabeth C. , Lehmann Brian D. , Abramson Vandana G. , Pietenpol Jennifer A. , Balko Justin M.
Published: February 2024

In vivo depletion of CD8 and NK cells and tumor endpoint MHC-I expression
Supplementary Tables 1 - 4 from Tumor Explants Elucidate a Cascade of Paracrine SHH, WNT, and VEGF Signals Driving Pancreatic Cancer Angiosuppression
Authors: Hasselluhn Marie C. , Decker-Farrell Amanda R. , Vlahos Lukas , Thomas Dafydd H. , Curiel-Garcia Alvaro , Maurer H. Carlo , Wasko Urszula N. , Tomassoni Lorenzo , Sastra Stephen A. , Palermo Carmine F. , Dalton Tanner C. , Ma Alice , Li Fangda , Tolosa Ezequiel J. , Hibshoosh Hanina , Fernandez-Zapico Martin E. , Muir Alexander , Califano Andrea , Olive Kenneth P.
Published: February 2024

Supplementary Table 1: Raw read counts per gene for bulk RNA-seq IPI-926 intervention study.

Raw read counts of matching biopsy (Bx) and necropsy (Nx) bulk RNA-seq samples after two days of treatment with vehicle or IPI-926.

Supplementary Table 2: Digestion buffer for single cell preparation.

List of reagents optimized for single cell digestion of KPC-derived tumors.

Supplementary Table 3: Single Cell RNA-seq Quality Control.

Overview of KPC-derived scRNA-seq samples, containing treatment information (vehicle or IPI-926; n=3 each), sequencing depth, detected genes, and detection of mitochondrial genes (MT%).

Supplementary Table 4: Network sizes in murine scRNA-seq data.

Number of regulatory proteins for which regulons were generated in each network type, in each cell type, from KPC mouse pancreatic tumors.
Supplementary Figure 7 from Tumor Explants Elucidate a Cascade of Paracrine SHH, WNT, and VEGF Signals Driving Pancreatic Cancer Angiosuppression
Authors: Hasselluhn Marie C. , Decker-Farrell Amanda R. , Vlahos Lukas , Thomas Dafydd H. , Curiel-Garcia Alvaro , Maurer H. Carlo , Wasko Urszula N. , Tomassoni Lorenzo , Sastra Stephen A. , Palermo Carmine F. , Dalton Tanner C. , Ma Alice , Li Fangda , Tolosa Ezequiel J. , Hibshoosh Hanina , Fernandez-Zapico Martin E. , Muir Alexander , Califano Andrea , Olive Kenneth P.
Published: February 2024

WNT Distribution and Expression of Downstream Targets.
Supplementary Figure 2 from Tumor Explants Elucidate a Cascade of Paracrine SHH, WNT, and VEGF Signals Driving Pancreatic Cancer Angiosuppression
Authors: Hasselluhn Marie C. , Decker-Farrell Amanda R. , Vlahos Lukas , Thomas Dafydd H. , Curiel-Garcia Alvaro , Maurer H. Carlo , Wasko Urszula N. , Tomassoni Lorenzo , Sastra Stephen A. , Palermo Carmine F. , Dalton Tanner C. , Ma Alice , Li Fangda , Tolosa Ezequiel J. , Hibshoosh Hanina , Fernandez-Zapico Martin E. , Muir Alexander , Califano Andrea , Olive Kenneth P.
Published: February 2024

IPI-926 treatment alters cellular composition in the tumor microenvironment.
Supplementary Data Table S4 from Loss-of-Function but Not Gain-of-Function Properties of Mutant TP53 Are Critical for the Proliferation, Survival, and Metastasis of a Broad Range of Cancer Cells
Authors: Wang Zilu , Burigotto Matteo , Ghetti Sabrina , Vaillant François , Tan Tao , Capaldo Bianca D. , Palmieri Michelle , Hirokawa Yumiko , Tai Lin , Simpson Daniel S. , Chang Catherine , Huang Allan Shuai , Lieschke Elizabeth , Diepstraten Sarah T. , Kaloni Deeksha , Riffkin Chris , Huang David C.S. , Li Wai Suen Connie S.N. , Garnham Alexandra L. , Gibbs Peter , Visvader Jane E. , Sieber Oliver M. , Herold Marco J. , Fava Luca L. , Kelly Gemma L. , Strasser Andreas
Published: February 2024

Supplementary Table S4 showing the impact of removal of mutant TP53 in human cancer cell lines in vitro by CRISPR/Cas9 by mining the DepMap database
Supplementary Data Table S3 from Loss-of-Function but Not Gain-of-Function Properties of Mutant TP53 Are Critical for the Proliferation, Survival, and Metastasis of a Broad Range of Cancer Cells
Authors: Wang Zilu , Burigotto Matteo , Ghetti Sabrina , Vaillant François , Tan Tao , Capaldo Bianca D. , Palmieri Michelle , Hirokawa Yumiko , Tai Lin , Simpson Daniel S. , Chang Catherine , Huang Allan Shuai , Lieschke Elizabeth , Diepstraten Sarah T. , Kaloni Deeksha , Riffkin Chris , Huang David C.S. , Li Wai Suen Connie S.N. , Garnham Alexandra L. , Gibbs Peter , Visvader Jane E. , Sieber Oliver M. , Herold Marco J. , Fava Luca L. , Kelly Gemma L. , Strasser Andreas
Published: February 2024

Supplementary Table S3 showing the IC50 values of human cancer cell lines with or without removal of mutant TP53 treated with anti-cancer drugs
Supplementary Data Table S1 from Loss-of-Function but Not Gain-of-Function Properties of Mutant TP53 Are Critical for the Proliferation, Survival, and Metastasis of a Broad Range of Cancer Cells
Authors: Wang Zilu , Burigotto Matteo , Ghetti Sabrina , Vaillant François , Tan Tao , Capaldo Bianca D. , Palmieri Michelle , Hirokawa Yumiko , Tai Lin , Simpson Daniel S. , Chang Catherine , Huang Allan Shuai , Lieschke Elizabeth , Diepstraten Sarah T. , Kaloni Deeksha , Riffkin Chris , Huang David C.S. , Li Wai Suen Connie S.N. , Garnham Alexandra L. , Gibbs Peter , Visvader Jane E. , Sieber Oliver M. , Herold Marco J. , Fava Luca L. , Kelly Gemma L. , Strasser Andreas
Published: February 2024

Supplementary Table S1 showing statistical analysis of differences in the numbers of human cancer cells in vitro with or without removal of mutant TP53
Supplementary Data Figure S13 from Loss-of-Function but Not Gain-of-Function Properties of Mutant TP53 Are Critical for the Proliferation, Survival, and Metastasis of a Broad Range of Cancer Cells
Authors: Wang Zilu , Burigotto Matteo , Ghetti Sabrina , Vaillant François , Tan Tao , Capaldo Bianca D. , Palmieri Michelle , Hirokawa Yumiko , Tai Lin , Simpson Daniel S. , Chang Catherine , Huang Allan Shuai , Lieschke Elizabeth , Diepstraten Sarah T. , Kaloni Deeksha , Riffkin Chris , Huang David C.S. , Li Wai Suen Connie S.N. , Garnham Alexandra L. , Gibbs Peter , Visvader Jane E. , Sieber Oliver M. , Herold Marco J. , Fava Luca L. , Kelly Gemma L. , Strasser Andreas
Published: February 2024

Supplementary Figure S13 showing that mutant TP53 deficient human cancer cell lines retain the machinery to respond to the activation of wt TP53
Data from Allosteric PI3Kα Inhibition Overcomes On-target Resistance to Orthosteric Inhibitors Mediated by Secondary PIK3CA Mutations
Authors: Varkaris Andreas , Fece de la Cruz Ferran , Martin Elizabeth E. , Norden Bryanna L. , Chevalier Nicholas , Kehlmann Allison M. , Leshchiner Ignaty , Barnes Haley , Ehnstrom Sara , Stavridi Anastasia-Maria , Yuan Xin , Kim Janice S. , Ellis Haley , Papatheodoridi Alkistis , Gunaydin Hakan , Danysh Brian P. , Parida Laxmi , Sanidas Ioannis , Ji Yongli , Lau Kayao , Wulf Gerburg M. , Bardia Aditya , Spring Laura M. , Isakoff Steven J. , Lennerz Jochen K. , Del Vecchio Kathryn , Pierce Levi , Pazolli Ermira , Getz Gad , Corcoran Ryan B. , Juric Dejan
Published: February 2024

Abstract
PIK3CA mutations occur in ∼8% of cancers, including ∼40% of HR-positive breast cancers, where the PI3K-alpha (PI3Kα)-selective inhibitor alpelisib is FDA approved in combination with fulvestrant. Although prior studies have identified resistance mechanisms, such as PTEN loss, clinically acquired resistance to PI3Kα inhibitors remains poorly understood. Through serial liquid biopsies and rapid autopsies in 39 patients with advanced breast cancer developing acquired resistance to PI3Kα inhibitors, we observe that 50% of patients acquire genomic alterations within the PI3K pathway, including PTEN loss and activating AKT1 mutations. Notably, although secondary PIK3CA mutations were previously reported to increase sensitivity to PI3Kα inhibitors, we identified emergent secondary resistance mutations in PIK3CA that alter the inhibitor binding pocket. Some mutations had differential effects on PI3Kα-selective versus pan-PI3K inhibitors, but resistance induced by all mutations could be overcome by the novel allosteric pan-mutant-selective PI3Kα-inhibitor RLY-2608. Together, these findings provide insights to guide strategies to overcome resistance in PIK3CA-mutated cancers.
Significance:
In one of the largest patient cohorts analyzed to date, this study defines the clinical landscape of acquired resistance to PI3Kα inhibitors. Genomic alterations within the PI3K pathway represent a major mode of resistance and identify a novel class of secondary PIK3CA resistance mutations that can be overcome by an allosteric PI3Kα inhibitor.

See related commentary by Gong and Vanhaesebroeck, p. 204.

See related article by Varkaris et al., p. 240.

This article is featured in Selected Articles from This Issue, p. 201
Data from Alveolar Differentiation Drives Resistance to KRAS Inhibition in Lung Adenocarcinoma
Authors: Li Zhuxuan , Zhuang Xueqian , Pan Chun-Hao , Yan Yan , Thummalapalli Rohit , Hallin Jill , Torborg Stefan , Singhal Anupriya , Chang Jason C. , Manchado Eusebio , Dow Lukas E. , Yaeger Rona , Christensen James G. , Lowe Scott W. , Rudin Charles M. , Joost Simon , Tammela Tuomas
Published: February 2024

Abstract
Lung adenocarcinoma (LUAD), commonly driven by KRAS mutations, is responsible for 7% of all cancer mortality. The first allele-specific KRAS inhibitors were recently approved in LUAD, but the clinical benefit is limited by intrinsic and acquired resistance. LUAD predominantly arises from alveolar type 2 (AT2) cells, which function as facultative alveolar stem cells by self-renewing and replacing alveolar type 1 (AT1) cells. Using genetically engineered mouse models, patient-derived xenografts, and patient samples, we found inhibition of KRAS promotes transition to a quiescent AT1-like cancer cell state in LUAD tumors. Similarly, suppressing Kras induced AT1 differentiation of wild-type AT2 cells upon lung injury. The AT1-like LUAD cells exhibited high growth and differentiation potential upon treatment cessation, whereas ablation of the AT1-like cells robustly improved treatment response to KRAS inhibitors. Our results uncover an unexpected role for KRAS in promoting intratumoral heterogeneity and suggest that targeting alveolar differentiation may augment KRAS-targeted therapies in LUAD.
Significance:
Treatment resistance limits response to KRAS inhibitors in LUAD patients. We find LUAD residual disease following KRAS targeting is composed of AT1-like cancer cells with the capacity to reignite tumorigenesis. Targeting the AT1-like cells augments responses to KRAS inhibition, elucidating a therapeutic strategy to overcome resistance to KRAS-targeted therapy.

This article is featured in Selected Articles from This Issue, p. 201
Data from ESR1 F404 Mutations and Acquired Resistance to Fulvestrant in ESR1-Mutant Breast Cancer
Authors: Kingston Belinda , Pearson Alex , Herrera-Abreu Maria Teresa , Sim Li-Xuan , Cutts Rosalind J. , Shah Heena , Moretti Laura , Kilburn Lucy S. , Johnson Hannah , Macpherson Iain R. , Ring Alistair , Bliss Judith M. , Hou Yingwei , Toy Weiyi , Katzenellenbogen John A. , Chandarlapaty Sarat , Turner Nicholas C.
Published: February 2024

Abstract
Fulvestrant is used to treat patients with hormone receptor–positive advanced breast cancer, but acquired resistance is poorly understood. PlasmaMATCH Cohort A (NCT03182634) investigated the activity of fulvestrant in patients with activating ESR1 mutations in circulating tumor DNA (ctDNA). Baseline ESR1 mutations Y537S are associated with poor outcomes and Y537C with good outcomes. Sequencing of baseline and EOT ctDNA samples (n = 69) revealed 3/69 (4%) patients acquired novel ESR1 F404 mutations (F404L, F404I, and F404V), in cis with activating mutations. In silico modeling revealed that ESR1 F404 contributes to fulvestrant binding to estrogen receptor–alpha (ERα) through a pi-stacking bond, with mutations disrupting this bond. In vitro analysis demonstrated that single F404L, E380Q, and D538G models were less sensitive to fulvestrant, whereas compound mutations D538G + F404L and E380Q + F404L were resistant. Several oral ERα degraders were active against compound mutant models. We have identified a resistance mechanism specific to fulvestrant that can be targeted by treatments in clinical development.
Significance:
Novel F404 ESR1 mutations may be acquired to cause overt resistance to fulvestrant when combined with preexisting activating ESR1 mutations. Novel combinations of mutations in the ER ligand binding domain may cause drug-specific resistance, emphasizing the potential of similar drug-specific mutations to impact the efficacy of oral ER degraders in development.

This article is featured in Selected Articles from This Issue, p. 201
Data from Tumor Explants Elucidate a Cascade of Paracrine SHH, WNT, and VEGF Signals Driving Pancreatic Cancer Angiosuppression
Authors: Hasselluhn Marie C. , Decker-Farrell Amanda R. , Vlahos Lukas , Thomas Dafydd H. , Curiel-Garcia Alvaro , Maurer H. Carlo , Wasko Urszula N. , Tomassoni Lorenzo , Sastra Stephen A. , Palermo Carmine F. , Dalton Tanner C. , Ma Alice , Li Fangda , Tolosa Ezequiel J. , Hibshoosh Hanina , Fernandez-Zapico Martin E. , Muir Alexander , Califano Andrea , Olive Kenneth P.
Published: February 2024

Abstract
The sparse vascularity of pancreatic ductal adenocarcinoma (PDAC) presents a mystery: What prevents this aggressive malignancy from undergoing neoangiogenesis to counteract hypoxia and better support growth? An incidental finding from prior work on paracrine communication between malignant PDAC cells and fibroblasts revealed that inhibition of the Hedgehog (HH) pathway partially relieved angiosuppression, increasing tumor vascularity through unknown mechanisms. Initial efforts to study this phenotype were hindered by difficulties replicating the complex interactions of multiple cell types in vitro. Here we identify a cascade of paracrine signals between multiple cell types that act sequentially to suppress angiogenesis in PDAC. Malignant epithelial cells promote HH signaling in fibroblasts, leading to inhibition of noncanonical WNT signaling in fibroblasts and epithelial cells, thereby limiting VEGFR2-dependent activation of endothelial hypersprouting. This cascade was elucidated using human and murine PDAC explant models, which effectively retain the complex cellular interactions of native tumor tissues.
Significance:
We present a key mechanism of tumor angiosuppression, a process that sculpts the physiologic, cellular, and metabolic environment of PDAC. We further present a computational and experimental framework for the dissection of complex signaling cascades that propagate among multiple cell types in the tissue environment.

This article is featured in Selected Articles from This Issue, p. 201
Data from Receptor-interacting Protein Kinase 2 Is an Immunotherapy Target in Pancreatic Cancer
Authors: Sang Wenhua , Zhou Yiduo , Chen Haiyan , Yu Chengxuan , Dai Lisi , Liu Zhongkun , Chen Lang , Fang Yimin , Ma Panpan , Wu Xiangji , Kong Hao , Liao Wenting , Jiang Hong , Qian Junbin , Wang Da , Liu Yun-Hua
Published: February 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy because of its aggressive nature and the paucity of effective treatment options. Almost all registered drugs have proven ineffective in addressing the needs of patients with PDAC. This is the result of a poor understanding of the unique tumor–immune microenvironment (TME) in PDAC. To identify druggable regulators of immunosuppressive TME, we performed a kinome- and membranome-focused CRISPR screening using orthotopic PDAC models. Our data showed that receptor-interacting protein kinase 2 (RIPK2) is a crucial driver of immune evasion of cytotoxic T-cell killing and that genetic or pharmacologic targeting of RIPK2 sensitizes PDAC to anti–programmed cell death protein 1 (anti–PD-1) immunotherapy, leading to prolonged survival or complete regression. Mechanistic studies revealed that tumor-intrinsic RIPK2 ablation disrupts desmoplastic TME and restores MHC class I (MHC-I) surface levels through eliminating NBR1-mediated autophagy-lysosomal degradation. Our results provide a rationale for a novel combination therapy consisting of RIPK2 inhibition and anti–PD-1 immunotherapy for PDAC.
Significance:
PDAC is resistant to almost all available therapies, including immune checkpoint blockade. Through in vivo CRISPR screen, we identified that RIPK2 plays a crucial role in facilitating immune evasion by impeding antigen presentation and cytotoxic T-cell killing. Targeting tumor-intrinsic RIPK2 either genetically or pharmacologically improves PDAC to anti–PD-1 immunotherapy.

See related commentary by Liu et al., p. 208.

This article is featured in Selected Articles from This Issue, p. 201
Data from NKG2A Is a Therapeutic Vulnerability in Immunotherapy Resistant MHC-I Heterogeneous Triple-Negative Breast Cancer
Authors: Taylor Brandie C. , Sun Xiaopeng , Gonzalez-Ericsson Paula I. , Sanchez Violeta , Sanders Melinda E. , Wescott Elizabeth C. , Opalenik Susan R. , Hanna Ann , Chou Shu-Ting , Van Kaer Luc , Gomez Henry , Isaacs Claudine , Ballinger Tarah J. , Santa-Maria Cesar A. , Shah Payal D. , Dees Elizabeth C. , Lehmann Brian D. , Abramson Vandana G. , Pietenpol Jennifer A. , Balko Justin M.
Published: February 2024

Abstract
Despite the success of immune checkpoint inhibition (ICI) in treating cancer, patients with triple-negative breast cancer (TNBC) often develop resistance to therapy, and the underlying mechanisms are unclear. MHC-I expression is essential for antigen presentation and T-cell–directed immunotherapy responses. This study demonstrates that TNBC patients display intratumor heterogeneity in regional MHC-I expression. In murine models, loss of MHC-I negates antitumor immunity and ICI response, whereas intratumor MHC-I heterogeneity leads to increased infiltration of natural killer (NK) cells in an IFNγ-dependent manner. Using spatial technologies, MHC-I heterogeneity is associated with clinical resistance to anti-programmed death (PD) L1 therapy and increased NK:T-cell ratios in human breast tumors. MHC-I heterogeneous tumors require NKG2A to suppress NK-cell function. Combining anti-NKG2A and anti–PD-L1 therapies restores complete response in heterogeneous MHC-I murine models, dependent on the presence of activated, tumor-infiltrating NK and CD8+ T cells. These results suggest that similar strategies may enhance patient benefit in clinical trials.
Significance:
Clinical resistance to immunotherapy is common in breast cancer, and many patients will likely require combination therapy to maximize immunotherapeutic benefit. This study demonstrates that heterogeneous MHC-I expression drives resistance to anti–PD-L1 therapy and exposes NKG2A on NK cells as a target to overcome resistance.

This article is featured in Selected Articles from This Issue, p. 201
Data from Loss-of-Function but Not Gain-of-Function Properties of Mutant TP53 Are Critical for the Proliferation, Survival, and Metastasis of a Broad Range of Cancer Cells
Authors: Wang Zilu , Burigotto Matteo , Ghetti Sabrina , Vaillant François , Tan Tao , Capaldo Bianca D. , Palmieri Michelle , Hirokawa Yumiko , Tai Lin , Simpson Daniel S. , Chang Catherine , Huang Allan Shuai , Lieschke Elizabeth , Diepstraten Sarah T. , Kaloni Deeksha , Riffkin Chris , Huang David C.S. , Li Wai Suen Connie S.N. , Garnham Alexandra L. , Gibbs Peter , Visvader Jane E. , Sieber Oliver M. , Herold Marco J. , Fava Luca L. , Kelly Gemma L. , Strasser Andreas
Published: February 2024

Abstract
Mutations in the tumor suppressor TP53 cause cancer and impart poor chemotherapeutic responses, reportedly through loss-of-function, dominant-negative effects and gain-of-function (GOF) activities. The relative contributions of these attributes is unknown. We found that removal of 12 different TP53 mutants with reported GOFs by CRISPR/Cas9 did not impact proliferation and response to chemotherapeutics of 15 human cancer cell lines and colon cancer–derived organoids in culture. Moreover, removal of mutant TP53/TRP53 did not impair growth or metastasis of human cancers in immune-deficient mice or growth of murine cancers in immune-competent mice. DepMap mining revealed that removal of 158 different TP53 mutants had no impact on the growth of 391 human cancer cell lines. In contrast, CRISPR-mediated restoration of wild-type TP53 extinguished the growth of human cancer cells in vitro. These findings demonstrate that LOF but not GOF effects of mutant TP53/TRP53 are critical to sustain expansion of many tumor types.
Significance:
This study provides evidence that removal of mutant TP53, thereby deleting its reported GOF activities, does not impact the survival, proliferation, metastasis, or chemotherapy responses of cancer cells. Thus, approaches that abrogate expression of mutant TP53 or target its reported GOF activities are unlikely to exert therapeutic impact in cancer.

See related commentary by Lane, p. 211.

This article is featured in Selected Articles from This Issue, p. 201
Mutant p53 Gain-of-Function in the Spotlight: Are We Suffering a GOF Delusion?
Authors: Lane David P.
Published: February 2024

Mutant p53 proteins are often highly expressed in human cancers and have been thought to have oncogenic driver gain-of-function (GOF) properties. Wang and colleagues show, surprisingly, that this is not the case because removing the TP53-mutant gene from human and mouse cancer cells using CRISPR technology has no effect on cancer cell growth in vitro or in vivo.

See related article by Wang et al., p. 362 (10) .
Supplementary Table from Functional Heterogeneity in MET Pathway Activation in PDX Models of Osimertinib-resistant EGFR-driven Lung Cancer
Authors: Roper Nitin , El Meskini Rajaa , Maity Tapan , Atkinson Devon , Day Amanda , Pate Nathan , Cultraro Constance M. , Pack Svetlana , Zgonc Valerie , Weaver Ohler Zoe , Guha Udayan
Published: February 2024

Supplementary Table provides clinical, molecular and passaging details for the PDXs generated in this study
FIGURE 5 from Functional Heterogeneity in MET Pathway Activation in PDX Models of Osimertinib-resistant EGFR-driven Lung Cancer
Authors: Roper Nitin , El Meskini Rajaa , Maity Tapan , Atkinson Devon , Day Amanda , Pate Nathan , Cultraro Constance M. , Pack Svetlana , Zgonc Valerie , Weaver Ohler Zoe , Guha Udayan
Published: February 2024

Phospho-MET expression is an indicator of MET activity post-osimertinib treatment; and proposed clinical flow diagram for treating EGFR-mutant NSCLC with evidence of MET pathway activation after osimertinib resistance. Representative phospho-MET IHC, MET FISH images and MET FISH scoring from pre- and post-osimertinib resistant tumors from patient LAT028 (multiple spatially heterogenous post-osimertinib resistant tumors shown; A) and from patient LAT021 (B). Scale bars, 50 µm. C, Clinical flow diagram for osimertinib-resistant EGFR-mutant NSCLC with evidence of MET pathway activation.
FIGURE 3 from Functional Heterogeneity in MET Pathway Activation in PDX Models of Osimertinib-resistant EGFR-driven Lung Cancer
Authors: Roper Nitin , El Meskini Rajaa , Maity Tapan , Atkinson Devon , Day Amanda , Pate Nathan , Cultraro Constance M. , Pack Svetlana , Zgonc Valerie , Weaver Ohler Zoe , Guha Udayan
Published: February 2024

Osimertinib and savolitinib combination suppresses AKT signaling in MET amplified osimertinib-resistant EGFR-mutant NSCLC PDXs. EGFR and MET pathway protein expression in MET amplified (A) and MET polysomy (B) LAT006 PDXs treated with either vehicle, osimertinib, savolitinib, and osimertinib plus savolitinib. Bar graphs show the relative quantification of phosphorylated proteins normalized to total protein expression in MET amplified (C) and MET polysomy (D) LAT006 PDXs.
FIGURE 2 from Functional Heterogeneity in MET Pathway Activation in PDX Models of Osimertinib-resistant EGFR-driven Lung Cancer
Authors: Roper Nitin , El Meskini Rajaa , Maity Tapan , Atkinson Devon , Day Amanda , Pate Nathan , Cultraro Constance M. , Pack Svetlana , Zgonc Valerie , Weaver Ohler Zoe , Guha Udayan
Published: February 2024

Efficacy and determinants of response to osimertinib and savolitinib combination among osimertinib-resistant EGFR-mutant NSCLC PDX models with spatially and temporally heterogenous MET pathway activation. Tumor growth inhibition studies in MET polysomy (A) and MET amplified (B) PDXs. Dashed vertical lines delineate when treatment was stopped. Asterisks signify statistical significance between osimertinib and savolitinib combination and osimertinib alone treatment arms. P values were calculated by t test. P values < 0.05 were considered significant. C, Association between response to osimertinib and savolitinib combination and IHC features (phospho-MET, c-MET), copy number and FISH parameters (number of MET copies and MET/CEP7 ratio). Response is defined as >25 days until reaching tumor size endpoint in osimertinib and savolitinib combination compared with osimertinib treatment alone. Individual circles represent a unique tumor for each represented PDX model. D, Representative c-MET and phospho-MET IHC images of PDX tumors with and without response to osimertinib and savolitinib combination. Scale bars, 50 µm.
FIGURE 1 from Functional Heterogeneity in MET Pathway Activation in PDX Models of Osimertinib-resistant EGFR-driven Lung Cancer
Authors: Roper Nitin , El Meskini Rajaa , Maity Tapan , Atkinson Devon , Day Amanda , Pate Nathan , Cultraro Constance M. , Pack Svetlana , Zgonc Valerie , Weaver Ohler Zoe , Guha Udayan
Published: February 2024

Generation of spatial and temporally heterogenous osimertinib-resistant EGFR-mutant NSCLC PDX models and treatment study design. A, Schematic diagram of the prospective clinical trial of LAT for osimertinib-treated EGFR-mutant lung cancer (RT: radiotherapy). PDXs were generated from osimertinib-resistant tumor tissue either at first or second progression on osimertinib or after standard of care (S.O.C) therapy. B, Multi-region and temporal tumor samples from surgical resections or biopsies used for PDX generation are shown for each individual patient. Putative mechanism of resistance to osimertinib as evidenced by exome and or transcriptome sequencing (Roper et al., Cell Reports Medicine 2020) is shown below each set of PDXs. Color denotes timing of sample acquisition. Red: first progression on osimertinib; Green: second progression on osimertinib; Blue: progression on S.O.C treatment. C, Illustrations of PDX generation from 3 patients with EGFR-mutant lung cancer with MET polysomy by FISH (MET ≥ 4.0 and <6.0 copies/cell if MET/CEP7 ratio is <2) or MET amplification by FISH (MET/CEP7 ratio ≥2.0 or ≥6 MET copies per cell) as a mechanism of resistance to osimertinib. D, Study design for treatment with MET inhibitor (savolitinib) with a third-generation EGFR TKI (osimertinib). PDXs with spatial heterogeneity in MET pathway activation (LAT001_6B and LAT001_9B), PDXs with temporal heterogeneity in MET pathway activation (LAT006_2B and LAT006_0118) and an additional validation PDX (LAT015_6B) were treated with vehicle, osimertinib, savolitinib, and osimertinib plus savolitinib combination followed by assessment of efficacy and identification of predictive markers.
Data from Functional Heterogeneity in MET Pathway Activation in PDX Models of Osimertinib-resistant EGFR-driven Lung Cancer
Authors: Roper Nitin , El Meskini Rajaa , Maity Tapan , Atkinson Devon , Day Amanda , Pate Nathan , Cultraro Constance M. , Pack Svetlana , Zgonc Valerie , Weaver Ohler Zoe , Guha Udayan
Published: February 2024

Abstract
MET pathway activation is one of the most common mechanisms of resistance to osimertinib in EGFR-mutant non–small cell lung cancer (NSCLC). We previously demonstrated spatial and temporal heterogeneity in MET pathway activation upon osimertinib resistance in EGFR-mutant NSCLC; however, the functional relevance of these findings is unclear. Here, we generated 19 patient-derived xenografts (PDX) from 9 patients with multi-region and temporal sampling of osimertinib-resistant tumor tissue from patients with EGFR-mutant NSCLC. MET pathway activation was a putative mechanism of osimertinib resistance in 66% (n = 6/9) patients from whom PDXs were generated. Significant spatial and temporal heterogeneity in MET pathway activation was evident. Osimertinib-resistant PDXs with MET amplification by FISH (defined as MET/CEP7 ratio ≥2.0 or mean MET ≥ 6.0 copies/cell) and high-level phospho-MET, but not c-MET expression, had better responses to osimertinib and savolitinib combination than to osimertinib alone. MET polysomy tumors by FISH from both PDXs and patients had evidence of subclonal phospho-MET expression. Select MET polysomy PDX tumors with phospho-MET expression responded better to osimertinib and savolitinib combination than MET polysomy PDX tumors without phospho-MET expression. Our results suggest osimertinib and savolitinib combination is most effective for osimertinib-resistant EGFR-mutant tumors with MET pathway activation as evidenced by phospho-MET. As subclonal MET amplification may be evident in MET polysomy tumor progression, MET polysomy warrants close clinical follow-up with phospho-MET IHC in parallel with FISH diagnostic.
Significance:
Using a novel cohort of in vivo PDX models of MET pathway activation with acquired resistance to osimertinib in EGFR-mutant lung cancer, we demonstrate that phospho-MET may be a clinically relevant assay to guide treatment selection with osimertinib and savolitinib combination. In addition, our work shows that patients with MET polysomy tumors may have subclonal MET amplification and therefore require close follow up for the use of osimertinib and savolitinib combination.
Sarcopenia Does Not Impact the Outcome of Patients with Multiple Myeloma Consolidated with Autologous Hematopoietic Stem Cell Transplantation
Authors: Annibali Ombretta , Altomare Annamaria , Tomarchio Valeria , Rocchi Giulia , Mallio Carlo Augusto , Tafuri Maria Antonietta , Zobel Bruno Beomonte , Vincenzi Bruno , Guarino Michele Pier Luca , Rigacci Luigi , Avvisati Giuseppe
Published: February 2024

Introduction: Sarcopenia has been associated with chronic diseases and cancer. The aim of this study was to evaluate sarcopenia in multiple myeloma patients undergoing autologous stem cell transplantation. Methods: In 68 eligible patients, measurement of skeletal muscle area (cm2) on computed tomography scans at the level of the L3 vertebra (L3 SMI) was performed. Results: 37 (54%) patients were categorized as sarcopenic: 26 males with L3 SMI values <52.4 cm2/m2, and 11 women with L3 SMI values <38.9 cm2/m2. The majority of sarcopenic patients included were older than 60 years (69%, p = 0.0005), with BMI <25 (75%; p = 0.0000). A significant association was found between sarcopenia and Sorror score value >1 (p = 0.02). Conclusions: The Kaplan-Meier curve showed a median OS of 73.5 months for non-sarcopenic patients versus 86.5 months for sarcopenic patients, suggesting that sarcopenia is not an independent prognostic factor in this cohort of patients. Further prospective studies are needed to confirm these data.
Relationship of Blood Pressure, Health Behaviors, and New Diagnosis and Control of Hypertension in the BP-CHECK Study
Authors: Hall Yoshio N. , Anderson Melissa L. , McClure Jennifer B. , Ehrlich Kelly , Hansell Laurel D. , Hsu Clarissa W. , Margolis Karen L. , Munson Sean A. , Thompson Matthew J. , Green Beverly B.
Published: February 2024

BACKGROUND:

Undiagnosed hypertension and uncontrolled blood pressure (BP) are common and contribute to excess cardiovascular morbidity and mortality. We examined whether BP control, changes in BP, and patient behaviors and attitudes were associated with a new hypertension diagnosis.

METHODS:

We performed a post hoc analysis of 323 participants from BP-CHECK (Blood Pressure Checks for Diagnosing Hypertension), a randomized diagnostic study of BP measuring methods in adults without diagnosed hypertension with elevated BP recruited from 12 primary care clinics of an integrated health care system in Washington State during 2017 to 2019. All 323 participants returned a positive diagnostic test for hypertension based on 24-hour ambulatory BP monitoring and were followed for 6 months. We used linear regression to examine the relationships between a new hypertension diagnosis (primary independent variable) and differences in the change in study outcomes from baseline to 6-month.

RESULTS:

Mean age of study participants was 58.3 years (SD, 13.1), 147 (45%) were women, and 253 (80%) were of non-Hispanic White race. At 6 months, 154 of 323 (48%) participants had a new hypertension diagnosis of whom 88 achieved target BP control. Participants with a new hypertension diagnosis experienced significantly larger declines from baseline in BP (adjusted mean difference: systolic BP, −7.6 mm Hg [95% CI, −10.3 to −4.8]; diastolic BP, −3.8 mm Hg [95% CI, −5.6 to −2.0]) compared with undiagnosed peers. They were also significantly more likely to achieve BP control by 6 months compared with undiagnosed participants (adjusted relative risk, 1.5 [95% CI, 1.1 to 2.0]). At 6 months, 101 of 323 participants (31%) with a positive ambulatory BP monitoring diagnostic test remained with undiagnosed hypertension, uncontrolled BP, and no antihypertensive medications.

CONCLUSIONS:

Approximately one-third of participants with high BP on screening and ambulatory BP monitoring diagnostic testing remained with undiagnosed hypertension, uncontrolled BP, and no antihypertensive medications after 6 months. New strategies are needed to enhance integration of BP diagnostic testing into clinical practice.

REGISTRATION:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT03130257.
Zeyneb Hanım’s Vakıf: Property Substitution (istibdāl) in Ottoman Istanbul seen through an Eighteenth Century Imperial Edict from the Dominican Archives
Authors: de Obaldía Vanessa R.
Published: February 2024

In Ottoman Istanbul, a Muslim woman called Zeyneb Hanım who owned endowed and freehold properties undertook to transfer them in a process known as substitution (istibdāl). This study reveals details about the actor, her motivations, and her properties with their locations, dimensions, boundaries, and income, in addition to the legal processes and conditions of the property substitution through a single Ottoman archival source. A previously unpublished imperial edict (fermān) issued on evāsiṭ-i şaʿbān 1189/ 6–15 October 1775 and unusually preserved within Galata’s Dominican archives is the basis of this study.
Mormons Are No Longer a Majority in Utah: Causes, Consequences, and Implications for the Sociology of Religion
Authors: Cragun Ryan T. , Gull Bethany , Phillips Rick
Published: February 2024

This paper uses a sample of Utahans to estimate the percentage of the state belonging to The Church of Jesus Christ of Latter-day Saints (the LDS, or Mormon Church). We find that the Mormon share of Utah’s population is lower than is commonly believed. This finding has relevance for certain theories in the sociology of religion that make inferences about church growth and vitality based on the religious demography of Utah. We show how the process of secularization, changes in Mormon fertility, and shifts in migration into Utah combine to alter the religious landscape of the state. We close with a discussion of the implications of our findings for the sociology of religion.
A Contrastive Pragmatics Study of Invitations in British English and Japanese
Authors: Matsukawa Chisa
Published: February 2024

This study offers a cross-cultural pragmatics perspective on invitations. It explores invitation seQuences in a symmetrical invitation-refusal situation, performed by 20 female native speakers of British English and 20 female native speakers of Japanese, from a discursive approach using role plays. The qualitative analysis of the data obtained from the adapted version of conversation analysis revealed some similarities and differences in turn designs of the English and the Japanese invitations. Although pre-sequences were highly frequent in the English data, they were more so in the Japanese data. The analysis of the linguistic formats of the invitations in the two sets of data revealed that an approach to handle uncertainty seen in the cases where the invitation was initiated with a preface differed – the English speakers used a syntactic solution whereas the Japanese speakers used a sequential solution. These findings highlight the importance of analysing speech acts in situated interactions.
A new species of Ceiba (Malvaceae, Bombacoideae), previously confused with Ceiba speciosa
Authors: DRAWERT HEINZ ARNO , ANGULO ALEJANDRO A. , CATARI JUAN C.
Published: February 2024

Based on the review of herbarium specimens, geo-referenced live images, and field observations, a new species of the genus Ceiba (Malvaceae) is described. Ceiba camba, the new species, has previously been confused with other species in the Ceiba insignis complex, specially with C. speciosa, and went undifferentiated despite having a wide distribution in the lowlands of central-western South America and being quite common. However, the new species here described shows clear visible morphological differences from C. speciosa and the other members of the genus. The main similarities and differences with other morphologically and geographically close species of the C. insignis complex (C. chodatii, C. crispiflora, C. insignis, C. lupuna, C. pubiflora, C. speciosa) are discussed.
Taxonomic notes on Alpinia brevis and A. bambusifolia (Zingiberaceae)
Authors: YAN JIAWEI , CHEN YOUSHENG , LIU HUA , YI SIRONG , CHEN JUAN
Published: February 2024

The identities and nomenclature histories of two endemic gingers from China, viz. Alpinia brevis and A. bambusifolia, are reviewed. Alpinia brevis was previously thought to be a widespread species, distributed in Hainan, Guangxi and Yunnan, while A. bambusifolia was known to be endemic to Guangxi. Nevertheless, the results in this study suggest that the collections from Guangxi and Yunnan were misidentified as A. brevis, those of which from Guangxi should belong to A. jianganfeng or Globba aff. racemosa, while those from Yunnan should belong to A. bambusifolia. The treatment that A. nanchuanensis is a synonym of A. bambusifolia is supported by our studies. After this revision, A. brevis is restricted to Hainan, while A. bambusifolia occurs in Chongqing, Guangxi, Guizhou and Yunnan, China. Lectotype is designated for A. nanchuanensis here.
Porophyllum iruyense (Asteraceae: Tageteae), a new endemic species from the north of Salta Province, Argentina
Authors: ANZUINELLI MILAGROS , BARTOLI ADRIANA
Published: February 2024

A new species of the genus Porophyllum (Asteraceae: Tageteae), P. iruyense, is described and illustrated. Photographs of the plant in its habitat and morphological details are given. This new species is endemic to the extreme north of Salta Province, where it grows in the rocky soil of the Sierra Santa Victoria. Porophyllum iruyense is characterized by being a decumbent odoriferous gynodioecious herb, with petiolate and lanceolate to narrowly ovate leaves with marginal pellucid cavities, and dark purple corollas. This species is known by locals for its medicinal properties. A table is given to differentiate it from other species inhabiting in South America, which are also gynodioecious and have the same dark purple colour in their corollas.