DNA damage response signatures are associated with frontline chemotherapy response and routes of tumor evolution in extensive stage small cell lung cancer

Abstract

DNA damage; Frontline chemotherapy; Small cell lung cancer

Daño del ADN; Quimioterapia de primera línea; Cáncer de pulmón de células pequeñas

Dany de l'ADN; Quimioteràpia de primera línia; Càncer de pulmó de cèl·lules petites

Introduction A hallmark of small cell lung cancer (SCLC) is its recalcitrance to therapy. While most SCLCs respond to frontline therapy, resistance inevitably develops. Identifying phenotypes potentiating chemoresistance and immune evasion is a crucial unmet need. Previous reports have linked upregulation of the DNA damage response (DDR) machinery to chemoresistance and immune evasion across cancers. However, it is unknown if SCLCs exhibit distinct DDR phenotypes. Methods To study SCLC DDR phenotypes, we developed a new DDR gene analysis method and applied it to SCLC clinical samples, in vitro, and in vivo model systems. We then investigated how DDR regulation is associated with SCLC biology, chemotherapy response, and tumor evolution following therapy. Results Using multi-omic profiling, we demonstrate that SCLC tumors cluster into three DDR phenotypes with unique molecular features. Hallmarks of these DDR clusters include differential expression of DNA repair genes, increased replication stress, and heightened G2/M cell cycle arrest. SCLCs with elevated DDR phenotypes exhibit increased neuroendocrine features and decreased “inflamed” biomarkers, both within and across SCLC subtypes. Clinical analyses demonstrated treatment naive DDR status was associated with different responses to frontline chemotherapy. Using longitudinal liquid biopsies, we found that DDR Intermediate and High tumors exhibited subtype switching and coincident emergence of heterogenous phenotypes following frontline treatment. Conclusions We establish that SCLC can be classified into one of three distinct, clinically relevant DDR clusters. Our data demonstrates that DDR status plays a key role in shaping SCLC phenotypes and may be associated with different chemotherapy responses and patterns of tumor evolution. Future work targeting DDR specific phenotypes will be instrumental in improving patient outcomes.

This work was supported by: NIH/NCI CCSG P30-CA016672 (MD Anderson Bioinformatics Shared Resource, and the MD Anderson Institutional Tissue bank (ITB)); The University of Texas-Southwestern and MD Anderson Cancer Center Lung SPORE P50-CA070907 (JW, JVH, CMG, LAB); NIH/NCI R01-CA207295 (LAB); NIH/NCI U01-CA213273 (JVH, LAB); NIH/NCI R50-CA243698 (CAS); NIH/NCI U01-CA256780 (JVH, LAB); NIH/NCI U24-CA213274 (LAB); The Department of Defense LC210510 (LAB); the LUNGevity Foundation 2020–02 (CMG); CPRIT RP210159 (CMG); Andrew Sabin Family Foundation (CMG); NETRF (CMG); NIH/NCI T32-CA009666 (KC); Rexanna’s Foundation for Fighting Lung Cancer (JVH, LAB, CMG); Jeffrey Lee Cousins Endowed Fellowship in Lung Cancer Research (BBM); and generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shot Program (JVH, CMG, LAB). BBM is a TRIUMPH Fellow in the CPRIT Research Training Program (RP210028). This research includes work performed in the Single Cell Genomics Core Facility, which is supported in part by CPRIT Single Core grant RP180684. LAB also acknowledges philanthropic support from A.R.K., L.W.Y., M.J.A., R.B.N., K.E.N., J.O., J.K.R., B. & B.N, C.K., P.C.B., S.S., S.R., and W.A.B.