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

Robert J. Cardnell, Ying Feng, Lixia Diao, You Hong Fan, Fatemah Masrorpour, Jing Wang, Yuqiao Shen, Gordon Mills, John D. Minna, John V. Heymach, Lauren A. Byers

Research output: Contribution to journalArticle

102 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)6322-6328
Number of pages7
JournalClinical Cancer Research
Volume19
Issue number22
DOIs
StatePublished - Nov 15 2013
Externally publishedYes

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Small Cell Lung Carcinoma
Phosphatidylinositol 3-Kinases
DNA Repair
Proteomics
Proteins
Heterografts
Protein Array Analysis
Poly(ADP-ribose) Polymerase Inhibitors
talazoparib
Drug Resistance
Cisplatin
Neoplasms
Research Design
Biomarkers
Western Blotting
Enzyme-Linked Immunosorbent Assay
Breast Neoplasms
Cell Line
Growth
In Vitro Techniques

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Proteomic markers of DNA repair and PI3K pathway activation predict response to the PARP inhibitor BMN 673 in small cell lung cancer. / Cardnell, Robert J.; Feng, Ying; Diao, Lixia; Fan, You Hong; Masrorpour, Fatemah; Wang, Jing; Shen, Yuqiao; Mills, Gordon; Minna, John D.; Heymach, John V.; Byers, Lauren A.

In: Clinical Cancer Research, Vol. 19, No. 22, 15.11.2013, p. 6322-6328.

Research output: Contribution to journalArticle

Cardnell, RJ, Feng, Y, Diao, L, Fan, YH, Masrorpour, F, Wang, J, Shen, Y, Mills, G, Minna, JD, Heymach, JV & Byers, LA 2013, 'Proteomic markers of DNA repair and PI3K pathway activation predict response to the PARP inhibitor BMN 673 in small cell lung cancer', Clinical Cancer Research, vol. 19, no. 22, pp. 6322-6328. https://doi.org/10.1158/1078-0432.CCR-13-1975
Cardnell, Robert J. ; Feng, Ying ; Diao, Lixia ; Fan, You Hong ; Masrorpour, Fatemah ; Wang, Jing ; Shen, Yuqiao ; Mills, Gordon ; Minna, John D. ; Heymach, John V. ; Byers, Lauren A. / Proteomic markers of DNA repair and PI3K pathway activation predict response to the PARP inhibitor BMN 673 in small cell lung cancer. In: Clinical Cancer Research. 2013 ; Vol. 19, No. 22. pp. 6322-6328.
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AU - Feng, Ying

AU - Diao, Lixia

AU - Fan, You Hong

AU - Masrorpour, Fatemah

AU - Wang, Jing

AU - Shen, Yuqiao

AU - Mills, Gordon

AU - Minna, John D.

AU - Heymach, John V.

AU - Byers, Lauren A.

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N2 - 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.

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