Dynamic variations in epithelial-to-mesenchymal transition (EMT), ATM, and SLFN11 govern response to PARP inhibitors and cisplatin in small cell lung cancer.

C Allison Stewart,Karen Yu,Robert J Cardnell,Bonnie S Glisson,Jing Wang,Junya Fujimoto,Fatemah Masrorpour,Pan Tong,Yuqiao Shen,Rasha O Bara,Triparna Sen,John V Heymach,Don L Gibbons,Samrat T Kundu,Lerong Li,Yuanbin Ru,Ying Feng,Leonard Post ,Ignacio I Wistuba ,You Hong Fan ,Lauren A Byers

doi:10.18632/oncotarget.15338

Abstract

Small cell lung cancer (SCLC) is one of the most aggressive forms of cancer, with a 5-year survival <7%. A major barrier to progress is the absence of predictive biomarkers for chemotherapy and novel targeted agents such as PARP inhibitors. Using a high-throughput, integrated proteomic, transcriptomic, and genomic analysis of SCLC patient-derived xenografts (PDXs) and profiled cell lines, we identified biomarkers of drug sensitivity and determined their prevalence in patient tumors. In contrast to breast and ovarian cancer, PARP inhibitor response was not associated with mutations in homologous recombination (HR) genes (e.g., BRCA1/2) or HRD scores. Instead, we found several proteomic markers that predicted PDX response, including high levels of SLFN11 and E-cadherin and low ATM. SLFN11 and E-cadherin were also significantly associated with in vitro sensitivity to cisplatin and topoisomerase1/2 inhibitors (all commonly used in SCLC). Treatment with cisplatin or PARP inhibitors downregulated SLFN11 and E-cadherin, possibly explaining the rapid development of therapeutic resistance in SCLC. Supporting their functional role, silencing SLFN11 reduced in vitro sensitivity and drug-induced DNA damage; whereas ATM knockdown or pharmacologic inhibition enhanced sensitivity. Notably, SCLC with mesenchymal phenotypes (i.e., loss of E-cadherin and high epithelial-to-mesenchymal transition (EMT) signature scores) displayed striking alterations in expression of miR200 family and key SCLC genes (e.g., NEUROD1, ASCL1, ALDH1A1, MYCL1). Thus, SLFN11, EMT, and ATM mediate therapeutic response in SCLC and warrant further clinical investigation as predictive biomarkers.

Highlights

In patients with small cell lung cancer (SCLC), responses to frontline chemotherapy are rapidly overcome by drug resistance [1]
Of 170 proteins and/ or phosphorylated proteins quantified by reverse-phase protein array (RPPA), low ATM (FC=-2.32, P=0.009) and high Schlafen 11 (SLFN11) (FC=5.11, P=0.014) protein expression were the most significantly associated with talazoparib response in the patient-derived xenografts (PDXs) models (Figure 1B)
Protein biomarker results were further validated at the mRNA level which showed an association between talazoparib response and high SLFN11 (FC=38.82, P=0.031), low ATM (FC=-2.12, P=0.004), and low CHEK1 (FC=-1.86, P=0.003) expression in PDX models (Figure 1D)

Summary

Introduction

In patients with small cell lung cancer (SCLC), responses to frontline chemotherapy are rapidly overcome by drug resistance [1]. Unlike other forms of www.impactjournals.com/oncotarget lung cancer, there are currently no biomarkers to predict treatment response in SCLC. We and others have recently described an association between SLFN11 expression and sensitivity to various PARP inhibitors, including talazoparib and olaparib, in SCLC models [12,13,14]. Some models with low levels of SLFN11 respond to PARP inhibition, whereas others with relatively high levels are resistant [12, 13]. These findings suggest that SLFN11 is unlikely to be the only determinant of drug response in SCLC

Methods

Results

Conclusion