Proteomic Markers of DNA Repair and PI3K Pathway Activation Predict Response to the PARP Inhibitor BMN 673 in Small Cell Lung Cancer

• Published in: Clinical cancer research 2013-11, Vol.19 (22), p.6322-6328
• Main Authors: CARDNELL, Robert J, YING FENG, BYERS, Lauren A, LIXIA DIAO, FAN, You-Hong, MASRORPOUR, Fatemah, JING WANG, YUQIAO SHEN, MILLS, Gordon B, MINNA, John D, HEYMACH, John V
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Disease Models, Animal; DNA Repair - drug effects; Enzyme Activation - drug effects; Female; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Transplantation; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases - metabolism; Phthalazines - pharmacology; Phthalazines - therapeutic use; Pneumology; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Small Cell Lung Carcinoma - drug therapy; Small Cell Lung Carcinoma - metabolism; TOR Serine-Threonine Kinases - metabolism; Tumors; Tumors of the respiratory system and mediastinum; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-13-1975

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. 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. 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. 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.