4.8 Editorial Material

The promise and peril of KRAS G12C inhibitors

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Article Oncology

Clinical Acquired Resistance to KRASG12C Inhibition through a novel KRAS Switch-II Pocket Mutation and Polyclonal Alterations Converging on RAS-MAPK Reactivation

Noritaka Tanaka et al.

Summary: This study described a patient with KRAS(G12C) non-small cell lung cancer who developed polyclonal acquired resistance to MRTX849 treatment. The research identified 10 heterogeneous resistance alterations that converged to reactivate the RAS-MAPK signaling pathway. Additionally, a novel KRAS(Y96D) mutation affecting key protein-drug interactions and driving resistance was discovered.

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Acquired Resistance to KRASG12C Inhibition in Cancer

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Summary: A study of 38 patients with KRAS(G12C)-mutant cancers treated with adagrasib revealed diverse mechanisms of acquired resistance in 45% of them, including various mutations and bypass mechanisms. New therapeutic strategies are needed to overcome this drug resistance.

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The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1

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K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions

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Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity

Till Maurer et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2012)