8P - Targeting antiapoptotic Bcl-2 proteins with highly specific BH3 mimetics in solid tumors

Background

Evasion of apoptosis is a hallmark of cancer survival and a reason for acquired resistance towards standard treatment, making it one of the challenges in modern cancer therapy. The antiapoptotic proteins Bcl-2, Bcl-x_L and Mcl-1, might be key to break such a resistance. In this study we evaluated the effects of highly specific inhibitors for Bcl-x_L (WEHI-539), Bcl-2 (ABT-199), and Mcl-1 (S63845) as well as dual inhibition of Bcl-x_L/Bcl-2 (ABT-263) in commonly occurring solid tumors.

Methods

Non-Small Cell Lung Cancer (NSCLC), Cholangiocarcinoma (CCA) and Breast Cancer cell lines were either exposed to fractionated photon radiation or chemotherapeutics (Epirubicin) as standard therapy with or without specific Bcl-2 protein inhibition. Protein expression was assessed via Western blots of cell lines. Effects on cell death were detected by flow cytometry measuring apoptosis.

Results

Dual Bcl-x_L/Bcl-2 inhibition led to significantly higher cell death induction in combination with radiotherapy in NSCLC and with Epirubicin in triple-negative breast cancer. Sole inhibition of Bcl-x_L caused an inferior but notable sensitization in both entities for standard therapy. In CCA, combination of fractionated photon beam radiation and specific Bcl-x_L inhibition showed a significant increase of cell death in all four employed cell lines. In addition, the triple-negative breast cancer cell line benefited synergistically from combined therapy with Mcl-1 inhibition and Epirubicin. In NSCLC, no correlation between basal expression of Bcl-2 family proteins and response to therapy was found and proteins were not regulated upon irradiation. Upregulation of Mcl-1 may play a role in promoting radioresistance after specific Bcl-2 and Mcl-1 inhibition. Following Epirubicin treatment, breast cancer cell lines showed a downregulation of antiapoptotic Bcl-2 protein expressions.

Conclusions

Our findings indicate that among antiapoptotic Bcl-2 proteins, targeting Bcl-x_L might break resistance to radiation in NSCLC, CCA and breast cancer in vitro. Especially for breast cancer, Mcl-1 could also be a promising target that needs to be further investigated.

Clinical trial identification

Editorial acknowledgement

None.

Legal entity responsible for the study

The authors.

Funding

AbbVie, Brigitte and Dr. Konstanze Wegener foundation, the German Research Foundation (DFG, grant No. KO5205/1-1 and KO5205/3-1) and the German Cancer Aid (DKH, grant No. 70113593).

Disclosure

All authors have declared no conflicts of interest.