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Loree JM , Wang Y , Syed MA , Sorokin AV , Coker O , Xiu J , Weinberg BA , VanderWalde AM , Tesfaye A , Raymond VM , Miron B , Tarcic G , Zelichov O , Broaddus RR , Ng PKS , Jeong KJ , Tsang YH , Mills GB , Overman MJ , Grothey A , Marshall JL , Kopetz S
Clinical and functional characterization of atypical KRAS/NRAS mutations in metastatic colorectal cancer
Clin Cancer Res. 2021 Aug 15;27(16) :4587-4598
PMID: 34117033    PMCID: PMC8364867    URL: https://www.ncbi.nlm.nih.gov/pubmed/34117033
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PURPOSE: Mutations in KRAS/NRAS (RAS) predict lack of anti-EGFR efficacy in metastatic colorectal cancer (mCRC). However, it is unclear if all RAS mutations have similar impact and atypical mutations beyond those in standard guidelines exist. EXPERIMENTAL DESIGN: We reviewed 7 tissue and 1 cfDNA cohorts of 9485 patients to characterize atypical RAS variants. Using an in-vitro cell-based assay (FACT), Ba/F3 transformation and in-vivo xenograft models of transduced isogenic clones, we assessed signaling changes across mutations. RESULTS: KRAS exon 2, extended RAS, and atypical RAS mutations were noted in 37.8%, 9.5%, and 1.2% of patients, respectively. Among atypical variants, KRAS L19F, Q22K and D33E occurred at prevalence {greater than or equal to}0.1%, while no NRAS codon 117/146 and only one NRAS codon 59 mutation was noted. Atypical RAS mutations had worse overall survival than RAS/BRAF wild-type mCRC (HR 2.90, 95% CI 1.24-6.80, P=0.014). We functionally characterized 114 variants with the FACT assay. All KRAS exon 2 and extended RAS mutations appeared activating. Of 57 atypical RAS variants characterized, 18 (31.6%) had signaling below wild-type, 23 (40.4%) had signaling between wild-type and activating control, and 16 (28.1%) were hyperactive beyond the activating control. Ba/F3 transformation (17/18 variants) and xenograft model (7/8 variants) validation was highly concordant with FACT results and activating atypical variants were those that occurred at highest prevalence in clinical cohorts. CONCLUSION: We provide best available evidence to guide treatment when atypical RAS variants are identified. KRAS L19F, Q22K, D33E and T50I are more prevalent than many guideline included RAS variants and functionally relevant.
1557-3265 Loree, Jonathan M Orcid: 0000-0001-8189-2132 Wang, Yucai Orcid: 0000-0002-1576-8341 Syed, Muddassir A Sorokin, Alexey V Coker, Oluwadara Xiu, Joanne Weinberg, Benjamin A Orcid: 0000-0002-0408-4817 VanderWalde, Ari M Orcid: 0000-0002-6842-2563 Tesfaye, Anteneh Orcid: 0000-0002-7518-1825 Raymond, Victoria M Orcid: 0000-0001-5223-0981 Miron, Benjamin Orcid: 0000-0002-5681-3110 Tarcic, Gabi Orcid: 0000-0001-7469-0647 Zelichov, Ori Broaddus, Russell R Ng, Patrick Kwok Shing Jeong, Kang Jin Tsang, Yiu Huen Mills, Gordon B Orcid: 0000-0002-0144-9614 Overman, Michael J Orcid: 0000-0001-5377-135x Grothey, Axel Marshall, John L Orcid: 0000-0002-3449-2344 Kopetz, Scott Journal Article United States Clin Cancer Res. 2021 Jun 11:clincanres.CCR-21-0180-E.2021. doi: 10.1158/1078-0432.CCR-21-0180.