Proteomic markers of DNA repair and PI3K pathway activation predict response to the PARP inhibitor BMN 673 in small cell lung cancer.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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: Robert J Cardnell, Ying Feng, Lixia Diao, You-Hong Fan, Fatemah Masrorpour, Jing Wang, Yuqiao Shen, Gordon B Mills, John D Minna, John V Heymach, Lauren A Byers
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 22 Pg. 6322-8 (Nov 15 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 24077350 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR.

Chemical References

• Phthalazines
• Poly(ADP-ribose) Polymerase Inhibitors
• talazoparib
• PARP1 protein, human
• Poly (ADP-Ribose) Polymerase-1
• MTOR protein, human
• TOR Serine-Threonine Kinases

Topics

• Animals
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• DNA Repair (drug effects)
• Disease Models, Animal
• Enzyme Activation (drug effects)
• Female
• Humans
• Lung Neoplasms (drug therapy, metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Transplantation
• Phosphatidylinositol 3-Kinases (metabolism)
• Phthalazines (pharmacology, therapeutic use)
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerase Inhibitors
• Small Cell Lung Carcinoma (drug therapy, metabolism)
• TOR Serine-Threonine Kinases (metabolism)
• Xenograft Model Antitumor Assays