Abstract 4608: Evaluation of the impact of homozygous MTAP truncations on the clinical activity of MTA-cooperative PRMT5 inhibitors

Abstract Homozygous deletion of the MTAP gene occurs in 10-15% of all human cancers. To benefit this large patient population, MTA-cooperative PRMT5 inhibitors, including TNG908, TNG462, and TNG456 were developed to leverage the synthetic lethal relationship between MTAP deletion and PRMT5 inhibition. Clinical trial eligibility for most MTA-cooperative PRMT5 inhibitors is restricted to patients with tumors with confirmed MTAP loss either detected by next-generation sequencing or immunohistochemistry. MTAP loss most commonly occurs as a co-deletion event with the proximal CDKN2A gene and the chromosomal 9p breakpoints are not uniform. Previously, we reported that homozygous loss of only the terminal exon (exon 8), an event reported to occur in only 0.5% of MTAP-deleted tumors, is insufficient for complete loss of MTAP activity in preclinical assays. Here, we report initial evidence for the clinical impact of MTAP truncations, as opposed to complete deletion, on the activity of MTA-cooperative PRMT5 inhibitors. Citation Format: Kimberly J. Briggs, Andre Mignault, Jordi Rodon, Victor Moreno, David Spigel, Capucine Baldini, Candace Haddox, Angela Hirbe, Ignacio Garrido-Laguna, Ibiayi Dagogo-Jack, Emiliano Calvo, Alexander Spira, Matthew R. Tonini, Douglas A. Whittington, Steven A. Lombardo, Binzhang Shen, Hannah Stowe, Shangtao Liu, Hongxiang Zhang, Satoshi Yoda, Brian Doyon, Wenhai Zhang, Minjie Zhang, Kevin M. Cottrell, Samuel Meier, Yi Yu, Teng Teng, Heidi Rego, Jennifer Morawiak, Heather DiBenedetto, Ellen Hooper, Adam Crystal. Evaluation of the impact of homozygous MTAP truncations on the clinical activity of MTA-cooperative PRMT5 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4608.

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Journal
Cancer Research
Published
2025-04-21
DOI
https://doi.org/10.1158/1538-7445.am2025-4608
Primary Topic
Cancer-related gene regulation
Type
article
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article

Abstract 4608: Evaluation of the impact of homozygous MTAP truncations on the clinical activity of MTA-cooperative PRMT5 inhibitors

Brian Doyon, Candace L. Haddox, Steven A. Lombardo, David R. Spigel et al.
Cancer Research
Cancer-related gene regulation
article

Abstract 4608: Evaluation of the impact of homozygous MTAP truncations on the clinical activity of MTA-cooperative PRMT5 inhibitors

Brian Doyon, Candace L. Haddox, Steven A. Lombardo, David R. Spigel, Kevin M. Cottrell, Jennifer Morawiak, Capucine Baldini, Ignacio Garrido‐Laguna, Jordi Rodón, Adam Crystal, Angela C. Hirbe, Ibiayi Dagogo‐Jack, Heather DiBenedetto, Douglas A. Whittington, Yi Yu, Alexander I. Spira, Satoshi Yoda, Matthew R. Tonini, Emiliano Calvo, Andre Mignault, Shangtao Liu, Ellen Hooper, Hongxiang Zhang, Binzhang Shen, Samuel R. Meier, Hannah Stowe, Minjie Zhang, Wenhai Zhang, Víctor Moreno, Kimberly J. Briggs, Teng Teng, Heidi Rego
article en

Abstract

Abstract Homozygous deletion of the MTAP gene occurs in 10-15% of all human cancers. To benefit this large patient population, MTA-cooperative PRMT5 inhibitors, including TNG908, TNG462, and TNG456 were developed to leverage the synthetic lethal relationship between MTAP deletion and PRMT5 inhibition. Clinical trial eligibility for most MTA-cooperative PRMT5 inhibitors is restricted to patients with tumors with confirmed MTAP loss either detected by next-generation sequencing or immunohistochemistry. MTAP loss most commonly occurs as a co-deletion event with the proximal CDKN2A gene and the chromosomal 9p breakpoints are not uniform. Previously, we reported that homozygous loss of only the terminal exon (exon 8), an event reported to occur in only 0.5% of MTAP-deleted tumors, is insufficient for complete loss of MTAP activity in preclinical assays. Here, we report initial evidence for the clinical impact of MTAP truncations, as opposed to complete deletion, on the activity of MTA-cooperative PRMT5 inhibitors. Citation Format: Kimberly J. Briggs, Andre Mignault, Jordi Rodon, Victor Moreno, David Spigel, Capucine Baldini, Candace Haddox, Angela Hirbe, Ignacio Garrido-Laguna, Ibiayi Dagogo-Jack, Emiliano Calvo, Alexander Spira, Matthew R. Tonini, Douglas A. Whittington, Steven A. Lombardo, Binzhang Shen, Hannah Stowe, Shangtao Liu, Hongxiang Zhang, Satoshi Yoda, Brian Doyon, Wenhai Zhang, Minjie Zhang, Kevin M. Cottrell, Samuel Meier, Yi Yu, Teng Teng, Heidi Rego, Jennifer Morawiak, Heather DiBenedetto, Ellen Hooper, Adam Crystal. Evaluation of the impact of homozygous MTAP truncations on the clinical activity of MTA-cooperative PRMT5 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4608.

Cancer ResearchVol. 85(8_Supplement_1)
The University of Texas MD Anderson Cancer Center (US), Washington University in St. Louis (US), University of Utah (US), Huntsman Cancer Institute (US), Massachusetts General Hospital (US), Tango Therapeutics (United States) (US), Sarah Cannon (US), Dana-Farber Cancer Institute (US), Hospital Universitario Fundación Jiménez Díaz (ES)
Openalex Percentile: Top 93%
Cancer-related gene regulation
DOISourceOpenAlex
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