Premium
Autophagy promotes escape from phosphatidylinositol 3‐kinase inhibition in estrogen receptor‐positive breast cancer
Author(s) -
Yang Wei,
Hosford Sarah R.,
Traphagen Nicole A.,
Shee Kevin,
Demidenko Eugene,
Liu Stephanie,
Miller Todd W.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201700477r
Subject(s) - autophagy , pi3k/akt/mtor pathway , estrogen receptor , antiestrogen , cancer research , breast cancer , pharmacology , tamoxifen , cancer , kinase , apoptosis , chemistry , biology , medicine , microbiology and biotechnology , biochemistry
Hyperactivation of the PI3K pathway has been implicated in resistance to antiestrogen therapies in estrogen receptor α (ER)‐positive breast cancer, prompting the development of therapeutic strategies to inhibit this pathway. Autophagy has tumor‐promoting and ‐suppressing roles and has been broadly implicated in resistance to anticancer therapies, including antiestrogens. Chloroquine (CQ) is an antimalarial and amebicidal drug that inhibits autophagy in mammalian cells and human tumors. Herein, we observed that CQ inhibited proliferation and autophagy in ER+ breast cancer cells. PI3K inhibition with GDC‐0941 (pictilisib) induced autophagy. Inhibition of autophagy using CQ or RNA interference potentiated PI3K inhibitor‐induced apoptosis. Combined inhibition of PI3K and autophagy effectively induced mitochondrial membrane depolarization, which required the BH3‐only proapoptotic proteins Bim and PUMA. Treatment with GDC‐0941, CQ, or the combination, significantly suppressed the growth of ER+ breast cancer xenografts in mice. In an antiestrogen‐resistant xenograft model, GDC‐0941 syn‐ ergized with CQ to provide partial, but durable, tumor regression. These findings warrant clinical evaluation of therapeutic strategies to target ER, PI3K, and autophagy for the treatment of ER+ breast cancer.—Yang, W., Hosford, S. R., Traphagen, N. A., Shee, K., Demidenko, E., Liu, S., Miller, T. W. Autophagy promotes escape from phos‐ phatidylinositol 3‐kinase inhibition in estrogen receptor‐positive breast cancer. FASEB J. 32, 1222‐1235 (2018). www.fasebj.org