Targeting DNA damage repair in small cell lung cancer and the biomarker landscape

Abstract

Small cell lung cancer (SCLC) is an aggressive malignancy that accounts for 14% of all lung cancer diagnoses. Despite decades of active research, treatment options for SCLC are limited and resistance to the few Food and Drug Administration (FDA) approved therapies develops rapidly. With no approved targeted agents to date, new therapeutic strategies are desperately needed. SCLC is characterized by high mutation burden, ubiquitous loss of TP53 and RB1, mutually exclusive amplification of MYC family members, thereby, high genomic instability. Studies in the past few years have demonstrated the potential of targeting the DNA damage response (DDR) pathway as a promising therapeutic strategy for SCLC. Inhibitors targeting DDR proteins have shown promise in preclinical models, and are under clinical investigation as single agents and in combination with cytotoxic therapies. Recent efforts to expand the therapeutic arsenal toward SCLC have focused in part on immune checkpoint inhibitors, such as agents targeting the receptor-ligand pair programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1). Clinical trials have confirmed activity of these agents in extensive stage (ES)-SCLC. However, while several patients had dramatic responses, overall response rates to immune checkpoint blockade (ICB) remain poor. As a result, there is an urgent need to develop rational combination therapies to enhance response rates to immunotherapy in SCLC. Identification of predictive biomarkers for patient stratification, identifying effective combinations to overcome adaptive resistance to DDR-targeted therapies and identifying strategies to enhance response to immunotherapy are areas of active investigation in SCLC.

Keywords: DNA damage response (DDR); biomarkers; immunotherapy; small cell lung cancer (SCLC).

Figure 1

Targeting DDR vulnerabilities of SCLC. Ubiquitous loss of TP53 and RB1 disrupts the G1-S cell cycle checkpoint SCLC making the cells dependent on G2-M cell cycle checkpoint for arrest upon DNA damage. MYC family amplifications and increased gene and protein expression of multiple DDR pathway molecules (indicated in green) suggest they may be effective targets in SCLC. DDR, DNA damage response; SCLC, small cell lung cancer; PARP, poly-ADP-ribose polymerase; ATM, ataxia telangiectasia-mutated; ATR, ataxia telangiectasia and Rad3-related protein.

Figure 2

Landscape of predictive biomarkers in SCLC. Recent preclinical studies identified predictive biomarkers of response to DDR-targeted therapies in SCLC. SLFN11 predicts sensitivity to PARP inhibitors and chemotherapy; AXL and/or EMT predict resistance to PARP and WEE1 targeting; high ATM expression predicts resistance to PARP and ATR-targeted therapies; high MYC expression and amplification predicts sensitivity to AURK and CHK1 inhibitors; high expression of the inhibitory Notch ligand Delta-like protein 3 (DLL3) predicts response to Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate. Approximate proportions for each biomarker are estimated based on a combination of reported patient tumor and/or patient-derived xenograft expression and (where available) response rates in specific biomarker-selected populations [DLL3 (PMID: 27932068), MYC (PMID: 28490518), SLFN11/ATM/EMT (PMID: 28212573)]. For example, while >50% DLL3 expression was noted in in over two-thirds of evaluated patient samples, an objective response was observed in only 18% of evaluable patients, suggesting proportion of SCLC sensitive to DLL3 is less than that which expresses high DLL3 (PMID: 27932068). SCLC, small cell lung cancer; SLFN11, schlafen 11; PARP, poly-ADP-ribose polymerase; DDR, DNA damage response; EMT, epithelial-mesenchymal transition; ATM, ataxia telangiectasia-mutated; ATR, ataxia telangiectasia and Rad3-related protein; AURK, Aurora kinase; CHK1, checkpoint kinase 1; PDX, patient-derived xenograft.