Unravelling the biology of SCLC: implications for therapy

Abstract

Small-cell lung cancer (SCLC) is an aggressive malignancy associated with a poor prognosis. First-line treatment has remained unchanged for decades, and a paucity of effective treatment options exists for recurrent disease. Nonetheless, advances in our understanding of SCLC biology have led to the development of novel experimental therapies. Poly [ADP-ribose] polymerase (PARP) inhibitors have shown promise in preclinical models, and are being clinically tested in combination with cytotoxic therapies and inhibitors of cell-cycle checkpoints. Preclinical data indicate that targeting of histone-lysine N-methyltransferase EZH2, a regulator of chromatin remodelling implicated in acquired therapeutic resistance, might augment and prolong chemotherapy responses. High expression of the inhibitory Notch ligand Delta-like protein 3 (DLL3) in most SCLCs has been linked to expression of Achaetescute homologue 1 (ASCL1; also known as ASH-1), a key transcription factor driving SCLC oncogenesis; encouraging preclinical and clinical activity has been demonstrated for an anti-DLL3-antibody–drug conjugate. The immune microenvironment of SCLC seems to be distinct from that of other solid tumours, with few tumour-infiltrating lymphocytes and low levels of the immune-checkpoint protein programmed cell death 1 ligand 1 (PD-L1). Nonetheless, immunotherapy with immune-checkpoint inhibitors holds promise for patients with this disease, independent of PD-L1 status. Herein, we review the progress made in uncovering aspects of the biology of SCLC and its microenvironment that are defining new therapeutic strategies and offering renewed hope for patients.

Targeting DNA damage in SCLC

“…There was no correlation between either biomarker with response although a trend to high SLFN11 expression and better overall survival was observed. SLFN11 is actively recruited to sites of DNA damage, inhibiting HR respectively) [54] and activating a cellular replication-stress response [55,56]. SLFN11 suppression has been associated with chemoresistance in SCLC models [57] and identified as a biomarker of PARP inhibitor response in SCLC PDX [44].…”

Identification of candidate responders for anti-PD-L1/PD-1 immunotherapy, Rova-T therapy, or EZH2 inhibitory therapy in small-cell lung cancer

“…Although it was reported that somatic genomic rearrangements of TP73 contribute to SCLC tumorigenesis (5), druggable gene aberrations are rarely identified. As there is no standard targeted therapy for SCLC, platinum-based doublet chemotherapy is recommended as first-line treatment for advanced SCLC; however, its effectiveness is limited (2). Therefore, there is a need for development of further treatment options for patients with SCLC.…”

“…Unlike therapy for lung adenocarcinoma (LADC), the treatment for SCLC has not significantly advanced over the last three decades (2)(3)(4). To understand the genomic landscape and identify candidate therapeutic targets in SCLC, large-scale genomic analyses were performed, which revealed that mutations in TP53 and RB1, and amplifications of the MYC family members SOX2 and SRSF1, have been recurrently identified (5)(6)(7)(8).…”

Perspectives in small cell lung cancer: is something moving?

“…In term of gene profiling these subgroups are clearly distinct but at present their meaning in term of prognosis and prediction of response to treatment are unclear (10). Many pathways have been studied, such as for example EGFR, RET, mTORC1 (11) and others are under evaluations, such as PARP, EZH2, WEE1 and epigenetic alterations (10). However no driver mutations have been identified and the heterogeneity at the basis of SCLC can be the reason of the failure of clinical trials with targeted therapies seen until now (11).…”

“…The so called "classic type" shows expression of ASCL1, the "variant type" expresses NEUROD1 and the third type is negative for both the two previous biomarkers. In term of gene profiling these subgroups are clearly distinct but at present their meaning in term of prognosis and prediction of response to treatment are unclear (10). Many pathways have been studied, such as for example EGFR, RET, mTORC1 (11) and others are under evaluations, such as PARP, EZH2, WEE1 and epigenetic alterations (10).…”