Dual-Target Strategy Shows Promise in Overcoming Drug Resistance in MCL

A new study suggests that simultaneously targeting 2 key survival pathways in mantle cell lymphoma (MCL) may offer a promising strategy to overcome treatment resistance in this aggressive form of blood cancer.¹

Although patients with MCL often respond initially to standard therapies, including Bruton’s tyrosine kinase inhibitors (BTKis) and proteasome inhibitors, most eventually develop resistance, leading to disease progression and relapse. It’s been estimated that up to one-third of patients are resistant to the BTKi ibrutinib (Imbruvica; Pharmacyclics and Janssen).² Median progression-free survival in these cases remains limited, underscoring the need for new treatment approaches.

In the new research, detailed in Blood Cancer Journal, investigators explored a novel, data-driven approach to identifying therapeutic targets in drug-resistant cancers. Using a computational pipeline designed to analyze pharmacogenomic data, the team identified 2 proteins—BIRC5 and MCL-1—as key drivers of tumor survival and resistance in B-cell malignancies.

Both proteins play central roles in preventing cancer cell death. BIRC5 inhibits apoptosis through multiple pathways, allowing malignant cells to evade programmed cell death, while MCL-1, a member of the BCL-2 family, supports tumor growth by maintaining mitochondrial integrity and blocking apoptotic signaling.

“Interestingly, BIRC5 and MCL-1 have both been reported to be over-expressed and strongly correlated with progression and survivability of patients with B-cell lymphomas, and their inhibition has shown potency in several hematological malignancies,” wrote the researchers.

To test whether targeting these proteins could improve treatment outcomes, the group evaluated 2 small-molecule inhibitors: YM155, which targets BIRC5, and S63845, which inhibits MCL-1. Experiments were conducted across multiple MCL cell lines, including models of both treatment-sensitive and drug-resistant disease. Results showed that each drug independently reduced cancer cell viability across all tested models, including those resistant to existing therapies. However, the most striking findings emerged when the drugs were used in combination.

When YM155 and S63845 were administered together, they demonstrated strong synergistic effects, significantly increasing cancer cell death compared with either agent alone. This dual-inhibition approach was particularly effective in cell lines representing relapsed or refractory disease, where treatment options are currently limited.

While the findings are based on preclinical models, the researchers underscored how they provide a compelling proof of concept for a new therapeutic strategy in MCL. By simultaneously targeting multiple survival pathways, dual inhibition of BIRC5 and MCL-1 may help overcome one of the greatest challenges in cancer treatment. The researchers cautioned that further studies, including clinical trials, will be needed to confirm safety and effectiveness in patients.

Further experiments by the group revealed that combining these agents with existing therapies, such as ibrutnib or proteasome inhibitor bortezomib (Velcade; Takeda), enhanced their effectiveness even further. Notably, the addition of YM155 or S63845 allowed for substantial reductions in the doses of standard therapies needed to achieve similar or greater anticancer effects.

Mechanistically, the study found that these treatments triggered apoptosis through mitochondrial dysfunction, a key pathway in programmed cell death. Laboratory assays confirmed increased activation of caspase enzymes and disruption of mitochondrial membrane potential—both hallmarks of apoptosis—following treatment.

The researchers also identified effects on cancer stem–like cells, which are often associated with treatment resistance. Drug-resistant MCL cells exhibited significantly elevated activity of aldehyde dehydrogenase (ALDH), a marker of stemness and aggressiveness. Treatment with YM155 reduced ALDH activity by more than 90% in resistant cells, suggesting the therapy may help eliminate particularly resilient tumor subpopulations.

Genomic analyses provided further insight into how these therapies work. Single-cell RNA sequencing revealed that a large proportion of tumor cells expressed high levels of both BIRC5 and MCL-1, supporting the rationale for dual targeting. Bulk RNA sequencing identified widespread changes in gene expression following treatment, including activation of tumor-suppressive and pro-apoptotic pathways and suppression of genes involved in cell cycle progression and cancer growth.

Additional pathway analyses showed that YM155 influenced key oncogenic pathways related to cell division and survival, while S63845 disrupted mitochondrial and metabolic processes. Together, these complementary mechanisms may explain the enhanced effectiveness of combination therapy, explained the researchers.

Importantly, analysis of patient-derived gene expression data suggested that the molecular changes induced by these treatments are associated with improved clinical outcomes, including overall survival and disease progression metrics.

References

1. Pfitzer J, Chakravarti S, Mazumder S, et al. Inhibition of BIRC5 and MCL-1 as a potential treatment strategy to overcome drug resistance in mantle cell lymphoma. Blood Cancer J. 2026;16(1):28. doi:10.1038/s41408-026-01467-1

2. Roué G, Sola B. Management of drug resistance in mantle cell lymphoma. Cancers. 202;12(6):1565. doi:10.3390/cancers12061565