by Keyword: Trail
Capuccino, L Valdez, Kleitke, T, Szokol, B, Svajda, L, Martin, F, Bonechi, F, Kreko, M, Azami, S, Montinaro, A, Wang, Y, Nikolov, V, Kaiser, L, Bonasera, D, Saggau, J, Scholz, T, Schmitt, A, Beleggia, F, Reinhardt, H C, George, J, Liccardi, G, Walczak, H, Tovari, J, Braegelmann, J, Montero, J, Sos, M L, Orfi, L, Peltzer, N, (2024). CDK9 inhibition as an effective therapy for small cell lung cancer Cell Death & Disease 15, 345 
Treatment-na & iuml;ve 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.
JTD Keywords: Apoptosis, Death, Dinaciclib, Mcl-, Models, P-tefb, Sch 727965, Trail, Tumors
