Combinatorial approaches for mitigating resistance to KRAS-targeted therapies
Open Access
- 23 September 2022
- journal article
- research article
- Published by Portland Press Ltd. in Biochemical Journal
- Vol. 479 (18), 1985-1997
- https://doi.org/10.1042/bcj20220440
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 upregulation 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.This publication has 56 references indexed in Scilit:
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