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Functional apoptosis profiling identifies MCL-1 and BCL-xL as prognostic markers and therapeutic targets in advanced
Denise Müller1, Paolo Mazzeo2, Raphael Koch2
1Institute of Pathology, University Medical Center Göttingen, University of Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany.
Background:
Multi-omics studies have shown a high and lack of common driver mutations in most thymomas (TH) and thymic carcinomas (TC) that hamper the development of novel treatment approaches. However, deregulation of apoptosis has been proposed as a common hallmark of TH and TC. BH3 profiling can be utilized to study the readiness of living cancer cells to undergo apoptosis and their dependency on pro-survival BCL-2 family proteins.
Methods:
We screened a cohort of 62 TH and TC patient samples for expression of BCL-2 family proteins and used the TC cell line 1889c and native TH for dynamic BH3 profiling and treatment with BH3 mimetics.
Results:
Immunohistochemical overexpression of MCL-1 and BCL-xL was a strong prognostic marker of TH and TC, and BH3 profiling indicated a strong dependency on MCL-1 and BCL-xL in TH. Single inhibition of MCL-1 resulted in increased binding of BIM to BCL-xL as an escape mechanism that the combined inhibition of both factors could overcome. Indeed, the inhibition of MCL-1 and BCL-xL in combination induced apoptosis in a caspase-dependent manner in untreated and MCL-1-resistant 1889c cells.
Conclusion:
TH and TC are exquisitely dependent on the pro-survival factors MCL-1 and BCL-xL, making them ideal candidates for co-inhibition by BH3 mimetics. Since TH show a heterogeneous dependency on BCL-2 family proteins, upfront BH3 profiling could select patients and tailor the optimal therapy with the least possible toxicity.
Insights
Thymomas and thymic carcinomas depend on MCL-1 and BCL-xL proteins for survival. BH3 profiling can identify dependencies and guide combination therapy with BH3 mimetics for improved patient outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Thymomas (TH) and thymic carcinomas (TC) lack common driver mutations, hindering targeted therapies.
- Deregulation of apoptosis is a shared characteristic of TH and TC.
- BH3 profiling assesses cancer cell apoptosis readiness and dependence on BCL-2 family proteins.
Purpose of the Study:
- To investigate the role of BCL-2 family proteins in TH and TC.
- To evaluate the efficacy of BH3 mimetics in treating TH and TC.
- To determine if BH3 profiling can guide personalized treatment strategies.
Main Methods:
- Screening of 62 TH and TC patient samples for BCL-2 family protein expression.
- Dynamic BH3 profiling of a TC cell line (1889c) and native TH.
- Treatment of cells with BH3 mimetics, including single and combined inhibition strategies.
Main Results:
- Overexpression of MCL-1 and BCL-xL correlated with poor prognosis in TH and TC.
- BH3 profiling revealed significant MCL-1 and BCL-xL dependency in TH.
- Combined inhibition of MCL-1 and BCL-xL induced apoptosis, overcoming resistance mechanisms.
Conclusions:
- TH and TC are highly dependent on MCL-1 and BCL-xL, making them targets for BH3 mimetic co-inhibition.
- BH3 profiling can personalize treatment by identifying patient-specific dependencies.
- This approach may lead to more effective and less toxic therapies for thymic malignancies.
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