Bcl-xL inhibition radiosensitizes PIK3CA/PTEN wild-type triple negative breast cancers with low Mcl-1 expression

• Published in: Cancer research communications 2022-07, Vol.2 (7), p.679-693
• Main Authors: Pesch, Andrea M, Chandler, Benjamin C, Michmerhuizen, Anna R, Carter, Hannah M, Hirsh, Nicole H, Wilder-Romans, Kari, Liu, Meilan, Ward, Tanner, Ritter, Cassandra L, Nino, Charles A, Jungles, Kassidy M, Pierce, Lori J, Rae, James M, Speers, Corey W
• Format: Article
• Language: English
• Subjects: bcl-X Protein - genetics; Cell Line, Tumor; Class I Phosphatidylinositol 3-Kinases - genetics; Female; Humans; Neoplasm Recurrence, Local; Proto-Oncogene Proteins c-bcl-2 - genetics; PTEN Phosphohydrolase - genetics; Triple Negative Breast Neoplasms - drug therapy
• ISSN: 2767-9764; 2767-9764
• DOI: 10.1158/2767-9764.crc-22-0024

Patients with radioresistant breast cancers, including a large percentage of women with triple negative breast cancer (TNBC), demonstrate limited response to radiation (RT) and increased locoregional recurrence; thus, strategies to increase the efficacy of RT in TNBC are critically needed. We demonstrate that pan Bcl-2 family inhibition (ABT-263, rER: 1.52-1.56) or Bcl-xL specific inhibition (WEHI-539, A-1331852; rER: 1.31-2.00) radiosensitized wild-type TNBC (MDA-MB-231, CAL-120) but failed to radiosensitize mutant TNBC (rER: 0.90 - 1.07; MDA-MB-468, CAL-51, SUM-159). Specific inhibition of Bcl-2 or Mcl-1 did not induce radiosensitization, regardless of status (rER: 0.95 - 1.07). In wild-type TNBC, pan Bcl-2 family inhibition or Bcl-xL specific inhibition with RT led to increased levels of apoptosis (p < 0.001) and an increase in cleaved PARP and cleaved caspase 3. CRISPR-mediated knockout in wild-type MDA-MB-231 and CAL-120 cells induced expression of pAKT/Akt and Mcl-1 and abolished Bcl-xL inhibitor-mediated radiosensitization (rER: 0.94 - 1.07). Similarly, Mcl-1 overexpression abolished radiosensitization in MDA-MB-231 and CAL-120 cells (rER: 1.02 - 1.04) but transient knockdown in CAL-51 cells promoted Bcl-xL-inhibitor mediated radiosensitization (rER 2.35 ± 0.05). , ABT-263 or A-1331852 in combination with RT decreased tumor growth and increased tumor tripling time (p < 0.0001) in wild-type TNBC cell line and patient-derived xenografts. Collectively, this study provides the preclinical rationale for early phase clinical trials testing the safety, tolerability, and efficacy of Bcl-xL inhibition and RT in women with wild-type wild-type TNBC at high risk for recurrence.