Padmanabhan Jaya, Saha Biswarup, Powell Chase, Mo Qianxing, Perez Bradford A, Chellappan Srikumar
Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, 1209 USF Magnolia Drive, Tampa, FL 33612, USA.
Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, 1209 USF Magnolia Drive, Tampa, FL 33612, USA.
Cancers (Basel). 2021 Aug 3;13(15):3906. doi: 10.3390/cancers13153906.
Non-small cell lung cancer has a 5-year survival rate of less than 12-15%, calling for the development of additional therapeutic strategies to combat this disease. Here we tested the efficacy of inhibiting cyclin-dependent kinase 9 (CDK9) on lung cancer cell lines with K-Ras and EGFR mutations and on lung cancer organoids. Three different CDK9 inhibitors reduced the viability and anchorage-independent growth of lung cancer cell lines at very low nanomolar to micromolar concentrations. CDK9 inhibition suppressed the expression of the anti-apoptotic protein, Mcl1, as well as the embryonic stem cell transcription factors, Sox2 and Sox9, which are pro-tumorigenic. In contrast, treatment with CDK9 inhibitors increased the levels of WT p53 and its downstream target p21 in K-Ras mutant cell lines. Furthermore, the CDK9 inhibitors could markedly reduce the viability of Osimertinib-resistant PC9 and AMG510-resistant H23 and H358 cells with comparable efficacy as the parental cells. CDK9 inhibitors could also significantly reduce the growth and viability of lung cancer organoids with high potency. Taken together, the data presented here strongly suggest that CDK9 inhibitors would be efficacious against K-Ras mutant and EGFR mutant NSCLCs, including those that develop resistance to targeted therapies.
非小细胞肺癌的5年生存率低于12% - 15%，因此需要开发更多治疗策略来对抗这种疾病。在此，我们测试了抑制细胞周期蛋白依赖性激酶9（CDK9）对具有K-Ras和EGFR突变的肺癌细胞系以及肺癌类器官的疗效。三种不同的CDK9抑制剂在极低的纳摩尔至微摩尔浓度下就能降低肺癌细胞系的活力和非锚定依赖性生长。CDK9抑制可抑制抗凋亡蛋白Mcl1以及具有促肿瘤作用的胚胎干细胞转录因子Sox2和Sox9的表达。相反，在K-Ras突变细胞系中，用CDK9抑制剂处理可增加野生型p53及其下游靶点p21的水平。此外，CDK9抑制剂能显著降低对奥希替尼耐药的PC9细胞以及对AMG510耐药的H23和H358细胞的活力，其疗效与亲代细胞相当。CDK9抑制剂还能高效显著降低肺癌类器官的生长和活力。综上所述，本文数据强烈表明CDK9抑制剂对K-Ras突变和EGFR突变的非小细胞肺癌有效，包括那些对靶向治疗产生耐药性的肿瘤。
