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Heterogeneous modulation of Bcl-2 family members and drug efflux mediate MCL-1 inhibitor resistance in multiple myeloma
- Source :
- Blood Advances. 5:4125-4139
- Publication Year :
- 2021
- Publisher :
- American Society of Hematology, 2021.
-
Abstract
- Antiapoptotic Bcl-2 family members have recently (re)emerged as key drug targets in cancer, with a tissue- and tumor-specific activity profile of available BH3 mimetics. In multiple myeloma, MCL-1 has been described as a major gatekeeper of apoptosis. This discovery has led to the rapid establishment of clinical trials evaluating the impact of various MCL-1 inhibitors. However, our understanding about the clinical impact and optimal use of MCL-1 inhibitors is still limited. We therefore explored mechanisms of acquired MCL-1 inhibitor resistance and optimization strategies in myeloma. Our findings indicated heterogeneous paths to resistance involving baseline Bcl-2 family alterations of proapoptotic (BAK, BAX, and BIM) and antiapoptotic (Bcl-2 and MCL-1) proteins. These manifestations depend on the BH3 profile of parental cells that guide the enhanced formation of Bcl-2:BIM and/or the dynamic (ie, treatment-induced) formation of Bcl-xL:BIM and Bcl-xL:BAK complexes. Accordingly, an unbiased high-throughput drug-screening approach (n = 528) indicated alternative BH3 mimetics as top combination partners for MCL-1 inhibitors in sensitive and resistant cells (Bcl-xL>Bcl-2 inhibition), whereas established drug classes were mainly antagonistic (eg, antimitotic agents). We also revealed reduced activity of MCL-1 inhibitors in the presence of stromal support as a drug-class effect that was overcome by concurrent Bcl-xL or Bcl-2 inhibition. Finally, we demonstrated heterogeneous Bcl-2 family deregulation and MCL-1 inhibitor cross-resistance in carfilzomib-resistant cells, a phenomenon linked to the MDR1-driven drug efflux of MCL-1 inhibitors. The implications of our findings for clinical practice emphasize the need for patient-adapted treatment protocols, with the tracking of tumor- and/or clone-specific adaptations in response to MCL-1 inhibition.
- Subjects :
- Drug
Stromal cell
media_common.quotation_subject
bcl-X Protein
03 medical and health sciences
0302 clinical medicine
Cell Line, Tumor
hemic and lymphatic diseases
medicine
Humans
Multiple myeloma
030304 developmental biology
media_common
0303 health sciences
business.industry
Bcl-2 family
Cancer
Hematology
medicine.disease
3. Good health
Pharmaceutical Preparations
Apoptosis
030220 oncology & carcinogenesis
Cancer research
Myeloid Cell Leukemia Sequence 1 Protein
Antimitotic Agent
Efflux
Multiple Myeloma
business
Subjects
Details
- ISSN :
- 24739537 and 24739529
- Volume :
- 5
- Database :
- OpenAIRE
- Journal :
- Blood Advances
- Accession number :
- edsair.doi.dedup.....3a4ea478f3f22662a9e88648ef15da78