PARP Inhibitor activity correlates with slfn11 expression and demonstrates synergy with temozolomide in small cell lung cancer

Benjamin H. Lok, Eric E. Gardner, Valentina E. Schneeberger, Andy Ni, Patrice Desmeules, Natasha Rekhtman, Elisa De Stanchina, Beverly A. Teicher, Nadeem Riaz, Simon N. Powell, John T. Poirier, Charles M. Rudin

Research output: Contribution to journalArticle

Abstract

Purpose: PARP inhibitors (PARPi) are a novel class of small molecule therapeutics for small cell lung cancer (SCLC). Identification of predictors of response would advance our understanding, and guide clinical application, of this therapeutic strategy. Experimental Design: Efficacy of PARP inhibitors olaparib, rucaparib, and veliparib, as well as etoposide and cisplatin in SCLC cell lines, and gene expression correlates, was analyzed using public datasets. HRD genomic scar scores were calculated from Affymetrix SNP 6.0 arrays. In vitro talazoparib efficacy was measured by cell viability assays. For functional studies, CRISPR/ Cas9 and shRNA were used for genomic editing and transcript knockdown, respectively. Protein levels were assessed by immunoblotting and immunohistochemistry (IHC). Quantitative synergy of talazoparib and temozolomide was determined in vitro. In vivo efficacy of talazoparib, temozolomide, and the combination was assessed in patient-derived xenograft (PDX) models. Results:Weidentified SLFN11, but notHRDgenomic scars, as a consistent correlate of response to all three PARPi assessed, with loss of SLFN11 conferring resistance to PARPi.Weconfirmed these findings in vivo across multiple PDX and defined IHC staining for SLFN11 as a predictor of talazoparib response. As temozolomide has activity in SCLC, we investigated combination therapy with talazoparib and found marked synergy in vitro and efficacy in vivo, which did not solely depend on SLFN11 or MGMT status. Conclusions: SLFN11 is a relevant predictive biomarker of sensitivity to PARP inhibitor monotherapy in SCLC and we identify combinatorial therapy with TMZ as a particularly promising therapeutic strategy that warrants further clinical investigation.

Original languageEnglish (US)
Pages (from-to)523-535
Number of pages13
JournalClinical Cancer Research
Volume23
Issue number2
DOIs
StatePublished - Jan 15 2017
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Lok, B. H., Gardner, E. E., Schneeberger, V. E., Ni, A., Desmeules, P., Rekhtman, N., De Stanchina, E., Teicher, B. A., Riaz, N., Powell, S. N., Poirier, J. T., & Rudin, C. M. (2017). PARP Inhibitor activity correlates with slfn11 expression and demonstrates synergy with temozolomide in small cell lung cancer. Clinical Cancer Research, 23(2), 523-535. https://doi.org/10.1158/1078-0432.CCR-16-1040