Combined inhibition of CDK4/6 and AKT is highly effective against the luminal androgen receptor (LAR) subtype of triple negative breast cancer.

Autor: Chica-Parrado MR; UT Southwestern Simmons Comprehensive Cancer Center, Dallas, TX, 75390, USA., Kim GM; UT Southwestern Simmons Comprehensive Cancer Center, Dallas, TX, 75390, USA; Yonsei University College of Medicine, Seoul, South Korea., Uemoto Y; UT Southwestern Simmons Comprehensive Cancer Center, Dallas, TX, 75390, USA., Napolitano F; UT Southwestern Simmons Comprehensive Cancer Center, Dallas, TX, 75390, USA., Lin CC; UT Southwestern Simmons Comprehensive Cancer Center, Dallas, TX, 75390, USA., Ye D; UT Southwestern Simmons Comprehensive Cancer Center, Dallas, TX, 75390, USA., Bikorimana E; UT Southwestern Simmons Comprehensive Cancer Center, Dallas, TX, 75390, USA., Fang Y; UT Southwestern Simmons Comprehensive Cancer Center, Dallas, TX, 75390, USA., Lee KM; UT Southwestern Simmons Comprehensive Cancer Center, Dallas, TX, 75390, USA; Dept. of Life Science, Hanyang University, Seoul, South Korea., Mendiratta S; UT Southwestern Simmons Comprehensive Cancer Center, Dallas, TX, 75390, USA., Hanker AB; UT Southwestern Simmons Comprehensive Cancer Center, Dallas, TX, 75390, USA. Electronic address: Ariella.Hanker@UTSouthwestern.edu., Arteaga CL; UT Southwestern Simmons Comprehensive Cancer Center, Dallas, TX, 75390, USA. Electronic address: Carlos.Arteaga@UTSouthwestern.edu.
Jazyk: angličtina
Zdroj: Cancer letters [Cancer Lett] 2024 Nov 01; Vol. 604, pp. 217219. Date of Electronic Publication: 2024 Sep 06.
DOI: 10.1016/j.canlet.2024.217219
Abstrakt: Luminal Androgen Receptor (LAR) triple-negative breast cancers (TNBC) express androgen receptors (AR), exhibit high frequency of PIK3CA mutations and intact RB. Herein, we investigated combined blockade of the CDK4/6 and PI3K signaling with palbociclib, alpelisib, and capivasertib, which inhibit CDK4/6, PI3Kα, and AKT1-3, respectively. The combination of palbociclib/capivasertib, but not palbociclib/alpelisib, synergistically inhibited proliferation of MDA-MB-453 and MFM-223 LAR cells [synergy score 7.34 (p = 5.81x10 -11 ) and 4.78 (p = 0.012), respectively]. The AR antagonist enzalutamide was inactive against MDA-MB-453, MFM-223, and CAL148 cells and did not enhance the efficacy of either combination. Palbociclib/capivasertib inhibited growth of LAR patient-derived xenografts more potently than palbociclib/alpelisib. Treatment of LAR cells with palbociclib suppressed phosphorylated-RB and resulted in adaptive phosphorylation/activation of S473 pAKT and AKT substrates GSK3β, PRAS40, and FoxO3a. Capivasertib blocked palbociclib-induced phosphorylation of AKT substrates more potently than alpelisib. Treatment with PI3Kβ inhibitors did not block phosphorylation of AKT substrates, suggesting that PI3Kβ did not mediate the adaptive response to CDK4/6 inhibition. Phosphokinase arrays of MDA-MB-453 cells treated with palbociclib showed time-dependent upregulation of PDGFRβ, GSK3β, STAT3, and STAT6. RNA silencing of PDGFRβ in palbociclib-treated MDA-MB-453 and MFM-223 cells blocked the upregulation of S473 pAKT, suggesting that the adaptive response to CDK4/6 blockade involves PDGFRβ signaling. Finally, treatment with palbociclib and the PDGFR inhibitor CP637451 arrested growth of MDA-MB-453 and MFM-223 cells to the same degree as palbociclib/capivasertib. These findings support testing the combination of CDK4/6 and AKT inhibitors in patients with LAR TNBC, and further investigation of PDGFR antagonists in this breast cancer subtype.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ariella B. Hanker received or has received research grants from Takeda and Lilly and nonfinancial support from Puma Biotechnology, Daiichi Sankyo, and Tempus. Carlos L. Arteaga receives or has received research grants from Pfizer, Lilly, and Takeda; holds minor stock options in Provista; serves or has served in an advisory role to Novartis, Merck, Lilly, Daiichi Sankyo, Taiho Oncology, OrigiMed, Puma Biotechnology, Immunomedics, AstraZeneca, Arvinas, and Sanofi; and reports scientific advisory board remuneration from the Susan G. Komen Foundation.
(Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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