No time to die? Intrinsic apoptosis signaling in hematopoietic stem and progenitor cells and therapeutic implications

Abstract

Purpose of review Dysregulated apoptosis contributes to the pathogenesis of many hematologic malignancies. BH3-mimetics, antagonists of antiapoptotic BCL-2 proteins, represent novel, and promising cancer drugs. While the acute myelosuppressive effects of Venetoclax, the first Food and Drug Administration approved BCL-2 inhibitor, are fairly well described, little is known about side effects of novel BH3-mimetics and effects of chronic Venetoclax treatment. Recent findings Highly relevant publications focused on the effects of acute and chronic Venetoclax therapy, with focus on cell-type specific adaptive mechanisms, the emergence of clonal hematopoiesis, and the selection of BAX-mutated hematopoietic cells in patients treated with Venetoclax for a long period. Important advances were made in understanding primary and secondary Venetoclax resistance and prediction of Venetoclax response. Combination therapies of BH3-mimetics targeting different BCL-2 proteins are highly anticipated. However, human stem and progenitors require both MCL-1 and BCL-XL for survival, and serious myelosuppressive effects of combined MCL-1/BCL-XL inhibition can be expected. Summary Long-term studies are indispensable to profile the chronic side effects of Venetoclax and novel BH3-mimetics and better balance their risk vs. benefit in cancer therapy. Combination therapies will be powerful, but potentially limited by severe myelosuppression. For precision medicine, a better knowledge of BCL-2 proteins in the healthy and diseased hematopoietic system is required.

Cell death in cancer chemotherapy using taxanes

“…However, cancer cells evolve to escape programmed cell death (Campbell and Leung, 2021;Hamilton et al, 2021;Neophytou et al, 2021;Hagenbourger et al, 2022;Zehnle et al, 2022), and this may be one of the several reasons that targeted or general cancer therapies have not yet gained overwhelming success.…”

“…However, the malignant cells eventually arise following clonal selection, and these persistent malignant cells become refractory to programmed cell death (Figure 2). Since cancer cells evolve to escape programmed cell death, and both apoptotic and necroptotic pathways are desensitized in the processes of transformation (Igney and Krammer, 2002;Mohammad et al, 2015;Campbell and Leung, 2021;Hamilton et al, 2021;Neophytou et al, 2021;Hagenbourger et al, 2022;Zehnle et al, 2022). Non-programmed cell death mechanisms may play important roles in strategies of cancer treatment (Figure 2).…”