Marasco Michelangelo, Kumar Dinesh, Garcia Borrego Santiago, Seale Tessa, Maddalena Giulia, Mezzadra Riccardo, Belanger Kylie, Cole Soren, Perez Brayan, Luan Wei, Mukherjee Radha, Aricescu Ilinca, Markov Vladimir, Zhu Yuxin, Arena Sabrina, Bardelli Alberto, de Stanchina Elisa, Lowe Scott W, Burkhart Richard A, Zimmerman Jacquelyn W, Yaeger Rona, Kopetz Scott E, Rosen Neal, Misale Sandra
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Cancer Discov. 2025 Jul 3;15(7):1392-1409. doi: 10.1158/2159-8290.CD-24-0614.
RAS genes are frequently mutated in cancer, often at codons 12 and 61. With the recent introduction of RAS inhibitors, we can now directly investigate the effects of specific RAS mutations in cancer cells. In this study, we demonstrate that in tumors with RASG12X mutations, mutant RAS can be activated by receptor tyrosine kinases (RTK), and PI3K activation is dependent on mutant RAS. Conversely, RASQ61X mutations activate the MAPK cascade independently of RTKs, and inhibition of RASQ61X impairs MAPK pathway activation but leaves the PI3K pathway unaffected. Our characterization of these distinct features of G12X and Q61X mutations suggests that co-inhibition of RAS and RTKs selectively inhibits the growth of RASG12X-mutant tumors, both in vitro and in vivo, regardless of the RAS isoform and tumor type. Additionally, our findings offer a mechanistic explanation for the increased frequency of RASQ61X mutations as a secondary resistance mechanism against EGFR inhibition in colorectal cancer.
RAS inhibition in multiple tumor types reveals the difference between G12 mutants and Q61 mutants in their cooperation with upstream regulators and downstream effectors to promote oncogenic signaling. Our findings provide the rationale for combinatorial approaches and contribute to explaining the nonuniform distribution of RAS mutations, de novo and at resistance.
RAS基因在癌症中经常发生突变，常见于密码子12和61处。随着RAS抑制剂的近期问世，我们现在能够直接研究特定RAS突变在癌细胞中的作用。在本研究中，我们证明，在具有RASG12X突变的肿瘤中，突变型RAS可被受体酪氨酸激酶（RTK）激活，且PI3K的激活依赖于突变型RAS。相反，RASQ61X突变独立于RTK激活MAPK级联反应，抑制RASQ61X会损害MAPK途径的激活，但对PI3K途径无影响。我们对G12X和Q61X突变这些不同特征的表征表明，无论RAS异构体和肿瘤类型如何，联合抑制RAS和RTK均可在体外和体内选择性抑制RASG12X突变型肿瘤的生长。此外，我们的数据为RASQ61X突变作为结直肠癌中针对EGFR抑制的继发性耐药机制频率增加提供了一种机制解释。
多种肿瘤类型中的RAS抑制揭示了G12突变体和Q61突变体在与上游调节因子和下游效应器协同促进致癌信号传导方面的差异。我们的研究结果为联合治疗方法提供了理论依据，并有助于解释RAS突变在原发和耐药时的非均匀分布。
