Department of Discovery Oncology, Genentech Inc., South San Francisco, CA, United States of America.
Department of Bioinformatics, Genentech Inc., South San Francisco, CA, United States of America.
PLoS One. 2018 Jun 18;13(6):e0199264. doi: 10.1371/journal.pone.0199264. eCollection 2018.
Mutant KRAS represents one of the most frequently observed oncogenes in NSCLC, yet no therapies are approved for tumors that express activated KRAS variants. While there is strong rationale for the use of MEK inhibitors to treat tumors with activated RAS/MAPK signaling, these have proven ineffective clinically. We therefore implemented a CRISPR screening approach to identify novel agents to sensitize KRAS mutant NSCLC cells to MEK inhibitor treatment. This approach identified multiple components of the canonical RAS/MAPK pathway consistent with previous studies. In addition, we identified MAPK7 as a novel, strong hit and validated this finding using multiple orthogonal approaches including knockdown and pharmacological inhibition. We show that MAPK7 inhibition attenuates the re-activation of MAPK signaling occurring following long-term MEK inhibition, thereby illustrating that MAPK7 mediates pathway reactivation in the face of MEK inhibition. Finally, genetic knockdown of MAPK7 combined with the MEK inhibitor cobimetinib in a mutant KRAS NSCLC xenograft model to mediate improved tumor growth inhibition. These data highlight that MAPK7 represents a promising target for combination treatment with MEK inhibition in KRAS mutant NSCLC.
KRAS 突变代表 NSCLC 中最常观察到的致癌基因之一，但尚无针对表达激活 KRAS 变体的肿瘤的批准疗法。尽管使用 MEK 抑制剂治疗激活 RAS/MAPK 信号的肿瘤具有很强的理论依据，但这些在临床上已被证明无效。因此，我们采用了 CRISPR 筛选方法来鉴定新型药物，以使 KRAS 突变型 NSCLC 细胞对 MEK 抑制剂治疗敏感。该方法鉴定了与先前研究一致的经典 RAS/MAPK 通路的多个成分。此外，我们还确定了 MAPK7 是一种新的、强大的命中靶点，并使用多种正交方法（包括敲低和药理学抑制）验证了这一发现。我们表明，MAPK7 抑制可减弱长期 MEK 抑制后发生的 MAPK 信号重新激活，从而表明 MAPK7 在面对 MEK 抑制时介导通路重新激活。最后，在 KRAS 突变型 NSCLC 异种移植模型中，MAPK7 的基因敲低与 MEK 抑制剂 cobimetinib 联合使用，可介导肿瘤生长抑制的改善。这些数据强调，MAPK7 代表了与 KRAS 突变型 NSCLC 的 MEK 抑制联合治疗的有前途的靶标。
