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

Autor:	Pesch AM; Department of Pharmacology, University of Michigan, Ann Arbor.; Department of Radiation Oncology, University of Michigan, Ann Arbor.; Rogel Cancer Center, University of Michigan, Ann Arbor., Chandler BC; Department of Radiation Oncology, University of Michigan, Ann Arbor.; Rogel Cancer Center, University of Michigan, Ann Arbor., Michmerhuizen AR; Department of Radiation Oncology, University of Michigan, Ann Arbor.; Rogel Cancer Center, University of Michigan, Ann Arbor.; Cellular and Molecular Biology Program, University of Michigan, Ann Arbor., Carter HM; Department of Radiation Oncology, University of Michigan, Ann Arbor., Hirsh NH; Department of Radiation Oncology, University of Michigan, Ann Arbor.; Rogel Cancer Center, University of Michigan, Ann Arbor., Wilder-Romans K; Department of Radiation Oncology, University of Michigan, Ann Arbor., Liu M; Department of Radiation Oncology, University of Michigan, Ann Arbor., Ward T; Department of Radiation Oncology, University of Michigan, Ann Arbor., Ritter CL; Department of Radiation Oncology, University of Michigan, Ann Arbor.; Rogel Cancer Center, University of Michigan, Ann Arbor., Nino CA; Department of Radiation Oncology, University of Michigan, Ann Arbor.; Rogel Cancer Center, University of Michigan, Ann Arbor.; Cellular and Molecular Biology Program, University of Michigan, Ann Arbor., Jungles KM; Department of Pharmacology, University of Michigan, Ann Arbor.; Department of Radiation Oncology, University of Michigan, Ann Arbor.; Rogel Cancer Center, University of Michigan, Ann Arbor., Pierce LJ; Department of Radiation Oncology, University of Michigan, Ann Arbor.; Rogel Cancer Center, University of Michigan, Ann Arbor., Rae JM; Department of Pharmacology, University of Michigan, Ann Arbor.; Rogel Cancer Center, University of Michigan, Ann Arbor.; Department of Internal Medicine, University of Michigan, Ann Arbor., Speers CW; Department of Radiation Oncology, University of Michigan, Ann Arbor.; Rogel Cancer Center, University of Michigan, Ann Arbor.
Jazyk:	angličtina
Zdroj:	Cancer research communications [Cancer Res Commun] 2022 Jul; Vol. 2 (7), pp. 679-693. Date of Electronic Publication: 2022 Jul 20.
DOI:	10.1158/2767-9764.crc-22-0024
Abstrakt:	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 PIK3CA/PTEN TNBC (MDA-MB-231, CAL-120) but failed to radiosensitize mutant PIK3CA/PTEN 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 PIK3CA/PTEN status (rER: 0.95 - 1.07). In wild-type PIK3CA/PTEN 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 PTEN knockout in wild-type PIK3CA/PTEN 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 MCL1 knockdown in CAL-51 cells promoted Bcl-xL-inhibitor mediated radiosensitization (rER 2.35 ± 0.05). In vivo , ABT-263 or A-1331852 in combination with RT decreased tumor growth and increased tumor tripling time (p < 0.0001) in PIK3CA/PTEN 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 PIK3CA/PTEN wild-type TNBC at high risk for recurrence. Competing Interests: The authors declare no potential conflicts of interest.
Databáze:	MEDLINE
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