Publication in Nature - Cell Death & Disease Journal

L. Valdez Capuccino, T. Kleitke, B. Szokol, L. Svajda, F. Martin, F. Bonechi, M. Krekó, S. Azami, A. Montinaro, Y. Wang, V. Nikolov, L. Kaiser, D. Bonasera, J. Saggau, T. Scholz, A. Schmitt, F. Beleggia, H. C. Reinhardt, J. George, G. Liccardi, H. Walczak, J. Tóvári, J. Brägelmann, J. Montero, …N. Peltzer

Abstract

Treatment-naïve small cell lung cancer (SCLC) is typically susceptible to standard-of-care chemotherapy consisting of cisplatin and etoposide recently combined with PD-L1 inhibitors. Yet, in most cases, SCLC patients develop resistance to first-line therapy and alternative therapies are urgently required to overcome this resistance. In this study, we tested the efficacy of dinaciclib, an FDA-orphan drug and inhibitor of the cyclin-dependent kinase (CDK) 9, among other CDKs, in SCLC. Furthermore, we report on a newly developed, highly specific CDK9 inhibitor, VC-1, with tumour-killing activity in SCLC. CDK9 inhibition displayed high killing potential in a panel of mouse and human SCLC cell lines. Mechanistically, CDK9 inhibition led to a reduction in MCL-1 and cFLIP anti-apoptotic proteins and killed cells, almost exclusively, by intrinsic apoptosis. While CDK9 inhibition did not synergise with chemotherapy, it displayed high efficacy in chemotherapy-resistant cells. In vivo, CDK9 inhibition effectively reduced tumour growth and improved survival in both autochthonous and syngeneic SCLC models. Together, this study shows that CDK9 inhibition is a promising therapeutic agent against SCLC and could be applied to chemo-refractory or resistant SCLC

CDK9 inhibition as an effective therapy for small cell lung cancer - Cell Death and Disease