by Keyword: Mcl-
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
Montero, J, Haq, R, (2022). Adapted to Survive: Targeting Cancer Cells with BH3 Mimetics Cancer Discovery 12, 1217-1232
A hallmark of cancer is cell death evasion, underlying suboptimal responses to chemotherapy, targeted agents, and immunotherapies. The approval of the anti apoptotic BCL2 antagonist venetoclax has fi nally validated the potential of targeting apoptotic pathways in patients with cancer. Nevertheless, pharmacologic modulators of cell death have shown markedly varied responses in preclinical and clinical studies. Here, we review emerging concepts in the use of this class of therapies. Building on these observations, we propose that treatment-induced changes in apoptotic dependency, rather than pretreatment dependencies, will need to be recognized and targeted to realize the precise deployment of these new pharmacologic agents. Signifi cance: Targeting antiapoptotic family members has proven effi cacious and tolerable in some cancers, but responses are infrequent, particularly for patients with solid tumors. Biomarkers to aid patient selection have been lacking. Precision functional approaches that overcome adaptive resistance to these compounds could drive durable responses to chemotherapy, targeted therapy, and immunotherapies.
JTD Keywords: Anti-apoptotic mcl-1, Bcl-x-l, Bim expression, Chemotherapy sensitivity, Combination strategies, Family proteins, Multiple-myeloma, Oblimersen sodium, Phase-i, Venetoclax resistance
