Acquired Resistance to KRAS(G12C) Inhibition in Cancer.
Acquired Resistance to KRAS(G12C) Inhibition in Cancer.
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DOI：
10.1056/nejmoa2105281
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发表时间：
2021-06-24
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影响因子：
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通讯作者：
Aguirre AJ
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作者：
Awad MM;Liu S;Rybkin II;Arbour KC;Dilly J;Zhu VW;Johnson ML;Heist RS;Patil T;Riely GJ;Jacobson JO;Yang X;Persky NS;Root DE;Lowder KE;Feng H;Zhang SS;Haigis KM;Hung YP;Sholl LM;Wolpin BM;Wiese J;Christiansen J;Lee J;Schrock AB;Lim LP;Garg K;Li M;Engstrom LD;Waters L;Lawson JD;Olson P;Lito P;Ou SI;Christensen JG;Jänne PA;Aguirre AJ
KRAS抑制剂Adagrasib和Sotorasib的临床试验显示，在KRAS甘氨酸到半胱氨酸氨基酸第12密码子(KRASG12C)替换的癌症中具有良好的活性。对这些疗法产生获得性耐药的机制目前尚不清楚。在接受阿达格西布单一治疗的KRASG12C突变癌症患者中，我们进行了基因组和组织学分析，将治疗前的样本与产生耐药性后获得的样本进行比较。以细胞为基础的实验被用来研究对KRASG12C抑制剂产生耐药性的突变。本研究共纳入38例患者：27例为非小细胞肺癌，10例为结直肠癌，1例为阑尾癌。在17名患者(45%的队列)中发现了对阿达格西布的假定耐药机制，其中7名患者(18%的队列)具有多个符合机制。获得性KRAS改变包括G12D/R/V/W、G13D、Q61H、R68S、H95D/Q/R、Y96C，以及KRASG12C等位基因的高水平扩增。获得性耐药旁路机制包括MET扩增；NRAS、BRAF、MAP2K1和RET的激活突变；涉及ALK、RET、BRAF、RAF1和FGFR3的致癌融合；以及NF1和PTEN的功能丧失突变。在9例肺腺癌患者中，有2例获得了配对的组织活检样本，观察到了向鳞状细胞癌的组织转化，但没有发现任何其他耐药机制。使用体外深突变扫描屏幕，我们系统地定义了对KRASG12C抑制剂产生耐药性的KRAS突变的图景。不同的基因组和组织学机制导致对共价KRASG12C抑制剂的耐药性，需要新的治疗策略来延缓和克服癌症患者的这种耐药性。(由Mirati Treeutics和其他公司资助；ClinicalTrials.gov编号，NCT03785249。)
Clinical trials of the KRAS inhibitors adagrasib and sotorasib have shown promising activity in cancers harboring KRAS glycine-to-cysteine amino acid substitutions at codon 12 (KRASG12C). The mechanisms of acquired resistance to these therapies are currently unknown. Among patients with KRASG12C-mutant cancers treated with adagrasib monotherapy, we performed genomic and histologic analyses that compared pretreatment samples with those obtained after the development of resistance. Cell-based experiments were conducted to study mutations that confer resistance to KRASG12C inhibitors. A total of 38 patients were included in this study: 27 with non–small-cell lung cancer, 10 with colorectal cancer, and 1 with appendiceal cancer. Putative mechanisms of resistance to adagrasib were detected in 17 patients (45% of the cohort), of whom 7 (18% of the cohort) had multiple coincident mechanisms. Acquired KRAS alterations included G12D/R/V/W, G13D, Q61H, R68S, H95D/Q/R, Y96C, and high-level amplification of the KRASG12C allele. Acquired bypass mechanisms of resistance included MET amplification; activating mutations in NRAS, BRAF, MAP2K1, and RET; oncogenic fusions involving ALK, RET, BRAF, RAF1, and FGFR3; and loss-of-function mutations in NF1 and PTEN. In two of nine patients with lung adenocarcinoma for whom paired tissue-biopsy samples were available, histologic transformation to squamous-cell carcinoma was observed without identification of any other resistance mechanisms. Using an in vitro deep mutational scanning screen, we systematically defined the landscape of KRAS mutations that confer resistance to KRASG12C inhibitors. Diverse genomic and histologic mechanisms impart resistance to covalent KRASG12C inhibitors, and new therapeutic strategies are required to delay and overcome this drug resistance in patients with cancer. (Funded by Mirati Therapeutics and others; ClinicalTrials.gov number, NCT03785249.)