Combinatorial approaches for mitigating resistance to KRAS-targeted therapies

Warren, Hannah R, Ross, Sarah J, Smith, Paul D, Coulson, Judy M ORCID: 0000-0003-2191-2001 and Prior, Ian A ORCID: 0000-0002-4055-5161 (2022) Combinatorial approaches for mitigating resistance to KRAS-targeted therapies. BIOCHEMICAL JOURNAL, 479 (18). pp. 1985-1997.

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Abstract

Approximately 15% of all cancer patients harbor mutated KRAS. Direct inhibitors of KRAS have now been generated and are beginning to make progress through clinical trials. These include a suite of inhibitors targeting the KRASG12C mutation commonly found in lung cancer. We investigated emergent resistance to representative examples of different classes of Ras targeted therapies. They all exhibited rapid reactivation of Ras signaling within days of exposure and adaptive responses continued to change over long-term treatment schedules. Whilst the gene signatures were distinct for each inhibitor, they commonly involved up-regulation of upstream nodes promoting mutant and wild-type Ras activation. Experiments to reverse resistance unfortunately revealed frequent desensitization to members of a panel of anti-cancer therapeutics, suggesting that salvage approaches are unlikely to be feasible. Instead, we identified triple inhibitor combinations that resulted in more durable responses to KRAS inhibitors and that may benefit from further pre-clinical evaluation.

Item Type:	Article
Uncontrolled Keywords:	Humans, Lung Neoplasms, Signal Transduction, Mutation, Proto-Oncogene Proteins p21(ras)
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	21 Sep 2022 10:10
Last Modified:	18 Jan 2023 20:41
DOI:	10.1042/BCJ20220440
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3164900