Abstract A37: Talazoparib predictive biomarker analysis in human small cell lung cancer cells and PDX tumors
Authors: Feng Ying , Yu Karen , Cardnell Robert , Ru Yuanbin (Kevin) , Wang Evelyn , Wang Jing , Post Leonard E. , Byers Lauren A. , Shen Yuqiao (Jerry) 
Published: May 2016

Background: Small cell lung cancer (SCLC) is an aggressive subtype of lung cancer, accounting for ∼15% of all lung cancer cases in US. Talazoparib (BMN 673) is a potent, specific PARP1/2 inhibitor that has demonstrated significant clinical activity in ovarian and breast cancer patients with deleterious germline BRCA1/2 mutations (ASCO 2014). Antitumor responses were also reported in SCLC patients treated with talazoparib (ASCO 2014). However, molecular determinants for SCLC response to talazoparib treatment have not been determined.

Method: in vitro: 38 human SCLC cell lines were screened for their sensitivity towards single-agent treatment with talazoparib or cisplatin. Sensitive vs. resistant cell lines were categorized based on median GI50 of 38 cell lines (as measured by generational growth inhibition approach) and 90% experimental maximum inhibition. Bioinformatics analysis was carried out to search for genomic features associated with talazoparib sensitivity, using CCLE genomic profiling data. in vivo: 12 human SCLC patient-derived xenograft (PDX) tumor models were established in immunocompromised mice. These PDX models were treated with either vehicle or talazoparib, and tumor growth was monitored by standard methods. Untreated tumor samples were collected from mice for molecular analyses (Myriad HRD assay, Foundation Medicine gene mutation analysis, reverse-phase protein array (RPPA), and Western blotting) to survey for talazoparib sensitivity biomarkers.

Result: The 38 SCLC lines showed a wide range of sensitivity to talazoparib (GI50 ranging from 2 nM to &gt;2000 nM, with median GI50 = 56 nM) and cisplatin treatment (GI50 ranging from 10 nM to &gt;10,000 nM). Sensitivity towards talazoparib and cisplatin are well correlated (Pearson r = 0.748). Differential gene expression analysis suggests sensitivity to talazoparib correlated well with high SLFN11 expression in SCLC lines (nominal p-value &lt; 0.001). The in vitro sensitivity results were confirmed in several cell line-derived xenograft models. In the SCLC PDX tumor screen, 3 of 12 PDX models showed tumor regression during talazoparib treatment with one complete response; 3 of 12 PDX tumors exhibited stable disease (SD)-like responses, while the remainder were resistant to talazoparib treatment. Gene mutation analysis indicates that all 12 SCLC PDX tumors have TP53 and/or RB1 mutations as expected for SCLC, but a correlation between mutations in the homologous recombination DNA repair genes (e.g. BRCA1, BRCA2, ATM) and response to talazoparib was not established in these models. Furthermore, no apparent relationship was found between talazoparib response and the Myriad HRD score in these SCLC PDX models, with all HRD scores being below the cutoff score associated with response to platinum treatment in breast and ovarian cancer. Protein expression analysis of PDX tumors is currently underway, and data will be presented at the meeting.

Citation Format: Ying Feng, Karen Yu, Robert Cardnell, Yuanbin (Kevin) Ru, Evelyn Wang, Jing Wang, Leonard E. Post, Lauren A. Byers, Yuqiao (Jerry) Shen. Talazoparib predictive biomarker analysis in human small cell lung cancer cells and PDX tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A37.