Inhibitors Targeting CDK9 Show High Efficacy against Osimertinib and AMG510 Resistant Lung Adenocarcinoma Cells

SIMPLE SUMMARY: Non-small cell lung cancer accounts for 80% of all lung cancer cases. While a subset of non-small cell lung cancer patients respond to immunotherapy, those who are treated with chemotherapy or targeted therapy develop resistance to the drugs. Thus, novel therapeutic strategies are needed to combat this disease. Here we show that inhibitors of the cyclin-dependent kinase 9 are highly effective in preventing the growth of a variety of lung cancer cell lines and lung cancer organoids with high potency. These inhibitors suppressed the expression of several genes like Sox2, Sox9, and Mcl1 that promote tumor growth, facilitating growth arrest. Since inhibitors of cyclin-dependent kinase 9 are undergoing clinical trials for hematological malignancies, our studies suggest that these inhibitors would be attractive candidates to combat non-small cell lung cancer. ABSTRACT: 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.