Mechanisms of resistance to KRAS G12C inhibition characterized
medwireNews: US researchers have identified diverse molecular and histologic mechanisms of acquired resistance to KRAS G12C inhibitors in people with cancer.
Presenting the findings at the virtual AACR Annual Meeting 2021, Mark Awad (Dana-Farber Cancer Institute, Boston, Massachusetts) explained that “covalent small molecule inhibitors of KRAS G12C, such as adagrasib and sotorasib, have shown promising antitumor activity in early-phase clinical trials,” but clinical mechanisms of resistance remain unknown.
The team therefore sequenced biopsy and/or circulating tumor DNA samples, collected at baseline and on progression, from 30 clinical trial participants – 23 with non-small-cell lung cancer and seven with colorectal cancer – who initially benefited from adagrasib treatment before progressing.
Putative resistance mechanisms were identified in 40% of the patients (single mechanism in 58%, multiple in 42%), and included genomic mechanisms such as secondary KRAS mutations (eg, G12D, Y96C, and H95R) and amplifications of KRAS G12C and MET as well as histologic mechanisms such as transformation from adenocarcinoma to squamous cell carcinoma.
“Novel combinatorial strategies will be necessary to delay or overcome resistance in KRAS G12C-mutant cancers,” concluded Awad.
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