dc.contributor.author | Vaclova, T | |
dc.contributor.author | Chakraborty, A | |
dc.contributor.author | Sherwood, J | |
dc.contributor.author | Ross, S | |
dc.contributor.author | Carroll, D | |
dc.contributor.author | Barrett, JC | |
dc.contributor.author | Downward, J | |
dc.contributor.author | de Bruin, EC | |
dc.coverage.spatial | England | |
dc.date.accessioned | 2022-07-12T14:52:38Z | |
dc.date.available | 2022-07-12T14:52:38Z | |
dc.date.issued | 2022-02-17 | |
dc.identifier | ARTN 2699 | |
dc.identifier | 10.1038/s41598-022-06369-3 | |
dc.identifier.citation | Scientific Reports, 2022, 12 (1), pp. 2699 - | |
dc.identifier.issn | 2045-2322 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/5210 | |
dc.identifier.eissn | 2045-2322 | |
dc.identifier.eissn | 2045-2322 | |
dc.identifier.doi | 10.1038/s41598-022-06369-3 | |
dc.description.abstract | 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. | |
dc.format | Electronic | |
dc.format.extent | 2699 - | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | NATURE PORTFOLIO | |
dc.relation.ispartof | Scientific Reports | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.subject | Carcinoma, Non-Small-Cell Lung | |
dc.subject | Cell Line, Tumor | |
dc.subject | Cell Survival | |
dc.subject | Enzyme Inhibitors | |
dc.subject | Humans | |
dc.subject | Lung Neoplasms | |
dc.subject | Mutation | |
dc.subject | Mutation Rate | |
dc.subject | Proto-Oncogene Proteins p21(ras) | |
dc.subject | Retrospective Studies | |
dc.title | Concomitant KRAS mutations attenuate sensitivity of non-small cell lung cancer cells to KRAS G12C inhibition. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2022-01-17 | |
dc.date.updated | 2022-07-12T14:50:09Z | |
rioxxterms.version | VoR | |
rioxxterms.versionofrecord | 10.1038/s41598-022-06369-3 | |
rioxxterms.licenseref.startdate | 2022-02-17 | |
rioxxterms.type | Journal Article/Review | |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/35177674 | |
pubs.issue | 1 | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology/Lung Cancer Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Lung Cancer Group | |
pubs.publication-status | Published online | |
pubs.volume | 12 | |
icr.researchteam | Lung Cancer Group | |
dc.contributor.icrauthor | Downward, Julian David Harry | |
icr.provenance | Deposited by Mr Arek Surman on 2022-07-12. Deposit type is initial. No. of files: 1. Files: Concomitant KRAS mutations attenuate sensitivity of non-small cell lung cancer cells to KRAS G12C inhibition.pdf | |