Functional apoptosis profiling identifies MCL-1 and BCL-xL as prognostic markers and therapeutic targets in advanced thymomas and thymic carcinomas

Abstract

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.

Oxidative Stress in Intervertebral Disc Degeneration: New Insights from Bioinformatic Strategies

“…The PRDX1 has been verified to be involved in the regulation of NK cells and protective autophagy in hepatocellular carcinoma [42]. The MCL1 was a famous antiapoptotic protein and could stimulate the progression and drug resistance of thymic carcinoma [43]. The TXNRD1 was a vital ferroptosis-related gene and has been approved to promote the invasion, progression, and metastasis of hepatocellular carcinoma [44].…”

“…The TXNRD1 was a vital ferroptosis-related gene and has been approved to promote the invasion, progression, and metastasis of hepatocellular carcinoma [44]. Based on previous studies [42][43][44], we made the assumption that PRDX1, MCL1, and TXNRD1 might participate in IDD progression via the regulation of oxidative stress, cell apoptosis, and immunity status, but future studies should be conducted to interpret the precise underlying mechanism. Moreover, to further explore the biological functions of OSIDDRGs, we performed the function enrichment analysis and identified several crucial KEGG pathways which might be involved in IDD.…”

Histogenetic and disease‐relevant phenotypes in thymic epithelial tumors (TETs): The potential significance for future TET classification

“…68 TETs are rare and may not be an attractive target for the pharmaceutical market. In addition, the in vitro culture of TETs, including thymic carcinomas, has not been successful, except for a few exceptional cell lines, [86][87][88][89][90] which hamper improving drug therapies for TETs. Because drugs sensitive to tuft cell-like SCLC have been intensively explored, 85 the application of treatment strategies for tuft cell-like SCLC to tuft cell-like thymic carcinomas could be considered.…”

Targeted therapies for cancer

“…Several other therapeutic targets have also showed promising results in preclinical models or in early-phase clinical trials. Müller et al identified MCL-1 and BCL-xL as biomarkers for survival and potential targets for the treatment of thymomas and thymic carcinomas [ 7 ]. Indeed, the development of next-generation sequencing has advanced our understanding on the molecular heterogeneity of cancers.…”