Details

Autor(en) / Beteiligte

• Vaclova, Tereza
• Chakraborty, Atanu
• Sherwood, James
• Ross, Sarah
• Carroll, Danielle
• Barrett, J. Carl
• Downward, Julian
• de Bruin, Elza C.

Titel

Concomitant KRAS mutations attenuate sensitivity of non-small cell lung cancer cells to KRAS G12C inhibition

Ist Teil von

• Scientific reports, 2022-02, Vol.12 (1), p.2699-2699, Article 2699

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• The development of covalent inhibitors against KRAS G12C represents a major milestone in treatment of RAS-driven cancers, especially in non-small cell lung cancer (NSCLC), where KRAS G12C is one of the most common oncogenic driver. Here we investigated if additional KRAS mutations co-occur with KRAS G12C (c.34G>T) in NSCLC tumours and if such mutation co-occurrence affects cellular response to G12C-specific inhibitors. Analysis of a large cohort of NSCLC patients whose tumours harboured KRAS mutations revealed co-occurring KRAS mutations in up to 8% of tumours with the KRAS c.34G>T mutation. KRAS c.35G>T was the most frequently co-occurring mutation, and could occur on the same allele (in cis) translating to a single mutant KRAS G12F protein, or on the other allele (in trans), translating to separate G12C and G12V mutant proteins. Introducing KRAS c.35G>T in trans in the KRAS G12C lung cancer model NCI-H358, as well as the co-occurrence in cis in the KRAS G12F lung cancer model NCI-H2291 led to cellular resistance to the G12C-specific inhibitor AZ’8037 due to continuing active MAPK and PI3K cascades in the presence of the inhibitor. Overall, our study provides a comprehensive assessment of co-occurring KRAS mutations in NSCLC and in vitro evidence of the negative impact of co-occurring KRAS mutations on cellular response to G12C inhibitors, highlighting the need for a comprehensive KRAS tumour genotyping for optimal patient selection for treatment with a KRAS G12C inhibitor.