Hata A N, Rowley S, Archibald H L, Gomez-Caraballo M, Siddiqui F M, Ji F, Jung J, Light M, Lee J S, Debussche L, Sidhu S, Sadreyev R I, Watters J, Engelman J A
Massachusetts General Hospital Cancer Center, Charlestown, MA, USA.
Department of Medicine, Harvard Medical School, Boston, MA, USA.
Oncogene. 2017 Nov 23;36(47):6581-6591. doi: 10.1038/onc.2017.258. Epub 2017 Aug 7.
There are currently no effective targeted therapies for KRAS mutant cancers. Therapeutic strategies that combine MEK inhibitors with agents that target apoptotic pathways may be a promising therapeutic approach. We investigated combining MEK and MDM2 inhibitors as a potential treatment strategy for KRAS mutant non-small cell lung cancers (NSCLC) and colorectal carcinomas that harbor wild-type TP53. The combination of pimasertib (MEK inhibitor) and SAR405838 (MDM2 inhibitor) was synergistic and induced the expression of PUMA and BIM, led to apoptosis and growth inhibition in vitro, and tumor regression in vivo. Acquired resistance to the combination commonly resulted from the acquisition of TP53 mutations, conferring complete resistance to MDM2 inhibition. In contrast, resistant clones exhibited marked variability in sensitivity to MEK inhibition, which significantly impacted sensitivity to subsequent treatment with alternative MEK inhibitor-based combination therapies. These results highlight both the potential promise and limitations of combining MEK and MDM2 inhibitors for treatment of KRAS mutant NSCLC and colorectal cancers.
目前，针对KRAS突变癌症尚无有效的靶向治疗方法。将MEK抑制剂与靶向凋亡途径的药物联合使用的治疗策略可能是一种有前景的治疗方法。我们研究了联合使用MEK和MDM2抑制剂作为携带野生型TP53的KRAS突变非小细胞肺癌（NSCLC）和结直肠癌的潜在治疗策略。匹美替尼（MEK抑制剂）和SAR405838（MDM2抑制剂）联合使用具有协同作用，可诱导PUMA和BIM的表达，在体外导致细胞凋亡和生长抑制，并在体内使肿瘤消退。对该联合治疗产生的获得性耐药通常源于TP53突变的获得，从而导致对MDM2抑制产生完全耐药。相比之下，耐药克隆对MEK抑制的敏感性表现出显著差异，这对后续使用基于替代MEK抑制剂的联合疗法的治疗敏感性产生了重大影响。这些结果凸显了联合使用MEK和MDM2抑制剂治疗KRAS突变NSCLC和结直肠癌的潜在前景和局限性。
