Targeting MCL-1 protein to treat cancer: opportunities and challenges

Tantawy, Shady I.; Timofeeva, Natalia; Sarkar, Aloke; Gandhi, Varsha

doi:10.3389/fonc.2023.1226289

Cited by 20 publications

(7 citation statements)

References 201 publications

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“…Regardless of these findings, multiple pharmaceutical companies generated MCL-1-specific inhibitors for treatment of MM, acute myeloid leukemia (AML) and B cell lymphoma that were tested in phase I clinical trials. Currently, most of these clinical trials have been put on FDA-instructed or voluntary hold due to dose-related cardiac toxicity 23 . Thus, although MCL-1 is a bona fide MM target, it should be inhibited in MM cells specifically to allow safe and effective treatment.…”

Section: Resultsmentioning

confidence: 99%

Engineering BCMA CAR T cells for myeloma-targeted cargo delivery

Kimman,

Cuenca,

Slomp

et al. 2024

Preprint

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Clinical responses with chimeric antigen receptor (CAR) T cells are encouraging, however, primary resistance and relapse after therapy prevent durable remission in a large fraction of cancer patients. One of the underlying causes comprises apoptosis resistance mechanisms in cancer cells that limit killing by CAR T cells. Therefore, we developed a technology that boosts tumor cell apoptosis induced by CAR T cells. We reveal that B cell maturation antigen (BCMA) CAR T cells equipped with a granzyme B-NOXA fusion construct improves killing of multiple myeloma (MM) cells, both in vitro and in a xenograft mouse model, by localizing NOXA to cytotoxic granules that are released into cancer cells upon contact. Since MM cells critically depend on MCL-1 expression, inhibition by its natural ligand NOXA effectively induces apoptosis. Overall, this strategy allows specific delivery of cargo into cancer cells and improves killing efficacy of CAR T cells in a tailor-made manner.

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Section: Resultsmentioning

confidence: 99%

Engineering BCMA CAR T cells for myeloma-targeted cargo delivery

Kimman,

Cuenca,

Slomp

et al. 2024

Preprint

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“…Clinically, MCL1 inhibitors are being explored in combination with various targeted agents including TKIs, mitotic inhibitors, autophagy inhibitors and anti-angiogenesis agents (69,70). Because increased MCL1 expression is frequently associated with resistance to multiple classes of therapeutic agents, MCL1 inhibitors make for ideal combination partners to improve and prolong therapeutic responses.…”

Section: Discussionmentioning

confidence: 99%

“…The clinical exploration of MCL1 inhibitors has been impeded by dose-limiting adverse events, including potential cardiac toxicity (69)(70)(71)(72). However, biomarker-driven patient selection strategies to improve therapeutic indices at lower dose levels are yet to be explored.…”

Section: Discussionmentioning

confidence: 99%

PBRM1 loss is associated with increased sensitivity to MCL1 and CDK9 inhibition in clear cell renal cancer

Fultang,

Schwab,

McAneny-Droz

et al. 2024

Front. Oncol.

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MCL1 is a member of the BCL2 family of apoptosis regulators, which play a critical role in promoting cancer survival and drug resistance. We previously described PRT1419, a potent, MCL1 inhibitor with anti-tumor efficacy in various solid and hematologic malignancies. To identify novel biomarkers that predict sensitivity to MCL1 inhibition, we conducted a gene essentiality analysis using gene dependency data generated from CRISPR/Cas9 cell viability screens. We observed that clear cell renal cancer (ccRCC) cell lines with damaging PBRM1 mutations displayed a strong dependency on MCL1. PBRM1 (BAF180), is a chromatin-targeting subunit of mammalian pBAF complexes. PBRM1 is frequently altered in various cancers particularly ccRCC with ~40% of tumors harboring damaging PBRM1 alterations. We observed potent inhibition of tumor growth and induction of apoptosis by PRT1419 in various preclinical models of PBRM1-mutant ccRCC but not PBRM1-WT. Depletion of PBRM1 in PBRM1-WT ccRCC cell lines induced sensitivity to PRT1419. Mechanistically, PBRM1 depletion coincided with increased expression of pro-apoptotic factors, priming cells for caspase-mediated apoptosis following MCL1 inhibition. Increased MCL1 activity has been described as a resistance mechanism to Sunitinib and Everolimus, two approved agents for ccRCC. PRT1419 synergized with both agents to potently inhibit tumor growth in PBRM1-loss ccRCC. PRT2527, a potent CDK9 inhibitor which depletes MCL1, was similarly efficacious in monotherapy and in combination with Sunitinib in PBRM1-loss cells. Taken together, these findings suggest PBRM1 loss is associated with MCL1i sensitivity in ccRCC and provide rationale for the evaluation of PRT1419 and PRT2527 for the treatment for PBRM1-deficient ccRCC.

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“…Myeloid cell leukemia-1 (MCL-1) is an anti-apoptotic protein that is a member of the BCL-2 family and is known to be overexpressed in various malignancies. The successful targeting of this pathway has been previously demonstrated with venetoclax in hematologic malignancies such as CLL and AML, and several MCL-1 inhibitors have been tested in the pre-clinical setting and are now entering in early-phase clinical trials for hematologic malignancies, including MDS [93].…”

Section: Potential Targetable Pathways: So Many Roadsmentioning

confidence: 99%

Myelodysplastic Neoplasms (MDS): The Current and Future Treatment Landscape

Karel,

Valburg,

Woddor

et al. 2024

Current Oncology

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Myelodysplastic neoplasms (MDS) are a heterogenous clonal disorder of hemopoietic stem cells characterized by cytomorphologic dysplasia, ineffective hematopoiesis, peripheral cytopenias and risk of progression to acute myeloid leukemia (AML). Our understanding of this disease has continued to evolve over the last century. More recently, prognostication and treatment have been determined by cytogenetic and molecular data. Specific genetic abnormalities, such as deletion of the long arm of chromosome 5 (del(5q)), TP53 inactivation and SF3B1 mutation, are increasingly associated with disease phenotype and outcome, as reflected in the recently updated fifth edition of the World Health Organization Classification of Hematolymphoid Tumors (WHO5) and the International Consensus Classification 2022 (ICC 2022) classification systems. Treatment of lower-risk MDS is primarily symptom directed to ameliorate cytopenias. Higher-risk disease warrants disease-directed therapy at diagnosis; however, the only possible cure is an allogenic bone marrow transplant. Novel treatments aimed at rational molecular and cellular pathway targets have yielded a number of candidate drugs over recent years; however few new approvals have been granted. With ongoing research, we hope to increasingly offer our MDS patients tailored therapeutic approaches, ultimately decreasing morbidity and mortality.

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Targeting MCL-1 protein to treat cancer: opportunities and challenges

Cited by 20 publications

References 201 publications

Engineering BCMA CAR T cells for myeloma-targeted cargo delivery

Engineering BCMA CAR T cells for myeloma-targeted cargo delivery

PBRM1 loss is associated with increased sensitivity to MCL1 and CDK9 inhibition in clear cell renal cancer

Myelodysplastic Neoplasms (MDS): The Current and Future Treatment Landscape

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