Mechanisms of Response and Tolerance to Active RAS Inhibition in KRAS-Mutant Non-Small Cell Lung Cancer.

Autor:	Araujo HA; Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Pechuan-Jorge X; Revolution Medicines, Redwood City, California., Zhou T; Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Do MT; Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Hu X; Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Rojas Alvarez FR; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Salvatierra ME; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Ibarguen HP; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Lee R; Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Raghulan R; Revolution Medicines, Redwood City, California., Shah H; Revolution Medicines, Redwood City, California., Moreno Ayala MA; Revolution Medicines, Redwood City, California., Chen K; Revolution Medicines, Redwood City, California., Tovbis Shifrin N; Revolution Medicines, Redwood City, California., Wu S; Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas., Solis Soto LM; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Negrao MV; Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Gibbons DL; Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Hong DS; Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Roth JA; Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas., Heymach JV; Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Zhang J; Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Jiang J; Revolution Medicines, Redwood City, California., Singh M; Revolution Medicines, Redwood City, California., Smith JAM; Revolution Medicines, Redwood City, California., Quintana E; Revolution Medicines, Redwood City, California., Skoulidis F; Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2024 Nov 01; Vol. 14 (11), pp. 2183-2208.
DOI:	10.1158/2159-8290.CD-24-0421
Abstrakt:	Resistance to inactive state-selective RASG12C inhibitors frequently entails accumulation of RASGTP, rendering effective inhibition of active RAS potentially desirable. Here, we evaluated the antitumor activity of the RAS(ON) multiselective tricomplex inhibitor RMC-7977 and dissected mechanisms of response and tolerance in KRASG12C-mutant non-small cell lung cancer (NSCLC). Broad-spectrum reversible RASGTP inhibition with or without concurrent covalent targeting of active RASG12C yielded superior and differentiated antitumor activity across diverse comutational KRASG12C-mutant NSCLC mouse models of primary or acquired RASG12C(ON) or RASG12C(OFF) inhibitor resistance. Interrogation of time-resolved single-cell transcriptional responses established an in vivo atlas of multimodal acute and chronic RAS pathway inhibition in the NSCLC ecosystem and uncovered a regenerative mucinous transcriptional program that supports long-term tumor cell persistence. In patients with advanced KRASG12C-mutant NSCLC, the presence of mucinous histologic features portended poor response to sotorasib or adagrasib. Our results have potential implications for personalized medicine and the development of rational RAS inhibitor-anchored therapeutic strategies. Significance: Our work reveals robust and durable antitumor activity of the preclinical RAS(ON) multiselective inhibitor RMC-7977 against difficult-to-treat subsets of KRASG12C-mutant NSCLC with primary or acquired RASG12C inhibitor resistance and identifies a conserved mucinous transcriptional state that supports RAS inhibitor tolerance. See related commentary by Marasco and Misale, p. 2018. (©2024 American Association for Cancer Research.)
Databáze:	MEDLINE
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