Supplementary Table S2 from Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers

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posted on 2024-06-04, 19:00 authored by Jingjing Jiang, Lingyan Jiang, Benjamin J. Maldonato, Yingyun Wang, Matthew Holderfield, Ida Aronchik, Ian P. Winters, Zeena Salman, Cristina Blaj, Marie Menard, Jens Brodbeck, Zhe Chen, Xing Wei, Michael J. Rosen, Yevgeniy Gindin, Bianca J. Lee, James W. Evans, Stephanie Chang, Zhican Wang, Kyle J. Seamon, Dylan Parsons, James Cregg, Abby Marquez, Aidan C.A. Tomlinson, Jason K. Yano, John E. Knox, Elsa Quintana, Andrew J. Aguirre, Kathryn C. Arbour, Abby Reed, W. Clay Gustafson, Adrian L. Gill, Elena S. Koltun, David Wildes, Jacqueline A.M. Smith, Zhengping Wang, Mallika Singh

Supplementary Table S2 shows cell panel screening data with a panel of 78 cancer cell lines harboring mutant and wild-type RAS selected for screening at Crown Bioscience.

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Revolution Medicines (REVOLUTION Medicines Inc)

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ARTICLE ABSTRACT

RAS-driven cancers comprise up to 30% of human cancers. RMC-6236 is a RAS(ON) multi-selective noncovalent inhibitor of the active, GTP-bound state of both mutant and wild-type variants of canonical RAS isoforms with broad therapeutic potential for the aforementioned unmet medical need. RMC-6236 exhibited potent anticancer activity across RAS-addicted cell lines, particularly those harboring mutations at codon 12 of KRAS. Notably, oral administration of RMC-6236 was tolerated in vivo and drove profound tumor regressions across multiple tumor types in a mouse clinical trial with KRASG12X xenograft models. Translational PK/efficacy and PK/PD modeling predicted that daily doses of 100 mg and 300 mg would achieve tumor control and objective responses, respectively, in patients with RAS-driven tumors. Consistent with this, we describe here objective responses in two patients (at 300 mg daily) with advanced KRASG12X lung and pancreatic adenocarcinoma, respectively, demonstrating the initial activity of RMC-6236 in an ongoing phase I/Ib clinical trial (NCT05379985). The discovery of RMC-6236 enables the first-ever therapeutic evaluation of targeted and concurrent inhibition of canonical mutant and wild-type RAS-GTP in RAS-driven cancers. We demonstrate that broad-spectrum RAS-GTP inhibition is tolerable at exposures that induce profound tumor regressions in preclinical models of, and in patients with, such tumors.This article is featured in Selected Articles from This Issue, p. 897

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Keywords

Gastrointestinal Cancers Lung Cancer Preclinical Models Small Molecule Agents Translational Research

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