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Ref Type Journal Article
PMID (34117033)
Authors 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
Title Clinical and Functional Characterization of Atypical KRAS / NRAS Mutations in Metastatic Colorectal Cancer.
Journal Vol Issue Date Pages Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research 27 16 2021 Aug 15 4587-4598 Clin Cancer Res
URL
Abstract Text 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. We reviewed 7 tissue and 1 cell-free DNA cohorts of 9,485 patients to characterize atypical RAS variants. Using an in vitro cell-based assay (functional annotation for cancer treatment), Ba/F3 transformation, and in vivo xenograft models of transduced isogenic clones, we assessed signaling changes across mutations. 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 ≥0.1%, whereas 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% confidence interval, 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. 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
NRAS A18T missense no effect - predicted NRAS A18T lies within a GTP-binding region of the Nras protein (UniProt.org). A18T results in nuclear translocation of Erk2 similar to wild-type Nras in an in vitro assay (PMID: 34117033), and therefore, is predicted to have no effect on Nras protein function.
NRAS G12R missense loss of function NRAS G12R is a hotspot mutation that lies within a GTP-binding region of the Nras protein (UniProt.org). G12R results in increased MAPK/ERK pathway activation in an in vitro assay, is transforming in culture (PMID: 34117033), and is predicted to lead to a loss of Nras protein function based on the effects of HRAS G12R (PMID: 3042780, PMID: 6092966).
NRAS G13R missense loss of function - predicted NRAS G13R is a hotspot mutation that lies within a GTP-binding region of the Nras protein (UniProt.org). G13R results in increased nuclear translocation of Erk2 compared to wild-type Kras in cell culture, is transforming in culture (PMID: 34117033), and can be predicted to lead to a loss of Nras protein function based on the effects of other NRAS G13 mutations.
NRAS K135N missense no effect NRAS K135N lies within the G domain of the Nras protein (PMID: 17384584). K135N results in similar cell proliferation and viability levels to wild-type Nras in cultured cells (PMID: 29533785, PMID: 34117033) and shows similar MAPK/ERK pathway activation to wild-type Nras in an in vitro assay (PMID: 34117033).
NRAS Q61K missense loss of function - predicted NRAS Q61K is a hotspot mutation that lies within a GTP-binding region of the Nras protein (UniProt.org). Q61K results in activation of downstream pathway signaling, increased survival, and transformation of cultured cells (PMID: 22718121, PMID: 34117033, PMID: 33431353), and is predicted to lead to a loss of Nras protein function based on the effects of HRAS Q61K (PMID: 3510078).
NRAS Q61R missense loss of function - predicted NRAS Q61R is a hotspot mutation that lies within a GTP-binding region of the Nras protein (UniProt.org). Q61R results in increased GTP-bound Nras, which leads to activation of Mapk signaling and cell transformation in culture (PMID: 16818621, PMID: 34117033), and is predicted to lead to a loss of GTPase activity based on the effect of HRAS Q61R (PMID: 3510078).
NRAS R164C missense no effect - predicted NRAS R164C lies within the G domain of the Nras protein (PMID: 17384584). R164C results in nuclear translocation of Erk2 similar to wild-type Nras in an in vitro assay (PMID: 34117033), and therefore, is predicted to have no effect on Nras protein function.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NRAS K135N colorectal cancer predicted - sensitive Cetuximab Preclinical - Cell line xenograft Actionable In a preclinical study, a cell line xenograft model of colorectal cancer expressing NRAS K135N demonstrated similar sensitivity to Erbitux (cetuximab) treatment compared to a NRAS wild-type model (PMID: 34117033). 34117033