Phosphorylation of ribosomal protein S6 confers PARP inhibitor resistance in BRCA1-deficient cancers.
Inhibition of poly(ADP-ribose) polymerase (PARP) is a promising therapeutic strategy for BRCA1 deficient cancers, however, the development of drug resistance limits clinical efficacy. Previously we found that the BRCA1-AKT1 pathway contributes to tumorigenesis and that the AKT1/mTOR is a novel therapeutic target for BRCA1-deficient cancers. Here, we report that phosphorylation of ribosomal protein S6, a mTOR downstream effector, is greatly increased in BRCA1 deficient cells resistant to PARP inhibition. Phosphorylation of S6 is associated with DNA damage and repair signaling during PARP inhibitor treatment. In BRCA1 deficient cells, expression of S6 lacking all five phosphorylatable sites renders the cells sensitive to PARP inhibitor and increases DNA damage signals. In addition, the S6 mutations reduce tumor formation induced by Brca1-deficiency in mice. Inhibition of S6 phosphorylation by rapamycin restores PARP sensitivity to resistant cells. Combined treatment with rapamycin and PARP inhibitor effectively suppresses BRCA1-deficient tumor growth in mice. These results provide evidence for a novel mechanism by which BRCA1 deficient cancers acquire drug resistance and suggest a new therapeutic strategy to circumvent resistance.
Cancer Biology Division, Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, MO 63108.
Chong-kui
CK
Sun
Fan
F
Zhang
Tao
T
Xiang
Qianming
Q
Chen
Tej K
TK
Pandita
Yuping
Y
Huang
Mickey C T
MC
Hu
Qin
Q
Yang
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005260:Female; D005455:Fluorescent Antibody Technique; D055879:Gene Knock-In Techniques; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D010766:Phosphorylation; D010793:Phthalazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D038601:Ribosomal Protein S6 / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D038601:Ribosomal Protein S6; C111164:BRAP protein, human; D044767:Ubiquitin-Protein Ligases; D020123:Sirolimus; C531550:olaparib