Proteomic markers of DNA repair and PI3K pathway activation predict response to the PARP inhibitor BMN 673 in small cell lung cancer.
OBJECTIVE
Small cell lung carcinoma (SCLC) is an aggressive malignancy affecting nearly 30,000 people annually in the United States. We have previously identified elevated PARP1 levels in SCLC and demonstrated in vitro sensitivity to the PARP inhibitors AZD 2281 and AG014699. Here, we evaluate activity of a novel, potent PARP inhibitor, BMN 673, and identify markers of response as a basis for developing predictive markers for clinical application.


METHODS
Inhibition of SCLC proliferation by BMN 673 was assayed in vitro and effects on tumor growth were measured in SCLC xenograft models. Protein expression and pathway activation was assessed by reverse phase protein array and western blot analysis. PARP inhibition was confirmed using a PAR ELISA.


RESULTS
We demonstrate striking, single agent activity of BMN 673 in SCLC cell lines and xenografts, with single agent BMN 673 exhibiting in vivo activity similar to cisplatin. Sensitivity to BMN 673 was associated with elevated baseline expression levels of several DNA repair proteins, whereas greater drug resistance was observed in SCLC models with baseline activation of the PI3K/mTOR pathway. Furthermore, we developed and confirmed these data with a novel "DNA repair score" consisting of a group of 17 DNA repair proteins.


CONCLUSIONS
Elevated expression of multiple DNA repair proteins, as well as a corresponding "DNA repair protein score," predict response to BMN 673 in in vitro SCLC models. These observations complement recent work in which PI3K inhibition sensitizes breast cancer models to PARP inhibition, suggesting cooperation between DNA repair and PI3K pathways.
Authors' Affiliations: Department of Thoracic/Head and Neck Medical Oncology; Bioinformatics and Computational Biology; Systems Biology, UT MD Anderson Cancer Center, Houston; Hamon Center for Therapeutic Oncology Research and the Simmons Comprehensive Cancer Center, UT Southwestern, Dallas, Texas; and Biomarin Pharmaceuticals Inc., Novato, California.
Robert J
RJ
Cardnell
Ying
Y
Feng
Lixia
L
Diao
You-Hong
YH
Fan
Fatemah
F
Masrorpour
Jing
J
Wang
Yuqiao
Y
Shen
Gordon B
GB
Mills
John D
JD
Minna
John V
JV
Heymach
Lauren A
LA
Byers
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects*; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010793:Phthalazines / Q000494:pharmacology / Q000627:therapeutic use*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D019869:Phosphatidylinositol 3-Kinases; D010793:Phthalazines; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D058570:TOR Serine-Threonine Kinases; C586365:talazoparib; C499320:PARP1 protein, human; C546842:MTOR protein, human