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 under clinical investigation 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 Achaete-scute 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.

Figure 1. Timeline of therapeutic advances for small-cell lung cancer (SCLC)

This timeline illustrates the paucity of new treatment options for patients with SCLC over the past three decades. The red-shaded boxes represent standard-of-care therapies that have been approved by the FDA; the yellow-shaded boxes represent therapies that have been recommended by the National Comprehensive Cancer Network (NCCN), but are not currently approved by the FDA. Since 1985, the cisplatin and etoposide chemotherapy regimen has remained the standard-of-care first-line systemic treatment for patients with extensive-stage (ES)-SCLC. Subsequent regimens, in which carboplatin or irinotecan substitute for cisplatin or etoposide, respectively, have comparable effectiveness, but differing toxicity profiles. Second-line therapies that are recommended in the NCCN guidelines include topoisomerase inhibitors, taxols, alkylating agents, and, since 2016, immunotherapy, although only topotecan is approved by the FDA for use in this setting. For limited-stage (LS)-SCLC, radiation treatment early in the course of chemotherapy is recommended, classically at a total dose of 45 Gy delivered in 30 twice-daily (b.i.d.) fractions of 1.5 Gy (over the course of 3 weeks), with additional prophylactic cranial irradiation (PCI). More recently, thoracic irradiation has been shown to be of benefit for some patients with ES-SCLC; however, the role of thoracic radiation and PCI in the treatment of ES-SCLC remains controversial.

Figure 2. Signalling pathways and physiological domains that are the focus of experimental targeted therapies for small-cell lung cancer (SCLC)

a | Dashed and solid lines indicate indirect and direct interactions, respectively. Proteins in green are typically upregulated in SCLCs compared with nonmalignant lung tissue, while those in red are downregulated or absent. Examples of the investigational molecularly targeted agents or antibody-based treatments targeting each signalling node are provided. b | The novel, investigational, targeted therapeutics for SCLC are predicated on five aspects of cancer biology. Immune-checkpoint blockade with antibodies targeting programmed cell death protein 1 (PD-1), programmed cell death 1 ligand 1 (PD-L1), and/or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) can prime the adaptive immune response to SCLC cells, whereas antibody-mediated blockade of the ‘don’t eat me’ protein CD47 can enable phagocytosis of tumour cells by macrophages. The use of small-molecule inhibitors of key regulators of the cell cycle, such as the protein kinases WEE1 and aurora kinase A, exploits the inherent lack of the G1/S-checkpoint activity resulting from loss of the tumour suppressors p53 and retinoblastoma-associated protein (Rb) in most SCLC cells. WEE1 regulates the G2/M cell-cycle checkpoint that is essential for ensuring the integrity of the genome in such cancer cells and, thus, inhibition of this kinase can lead to mitotic catastrophe and apoptosis, particularly if combined with DNA-damaging therapies. By contrast, aurora kinase A has essential roles in mitosis, and inhibitors of this protein results in cell-cycle arrest, preventing cell proliferation. Inhibitors of Notch have demonstrated antitumour effects in preclinical studies. Moreover, Delta-like protein 3 (DLL3), an inhibitory Notch ligand, is specifically upregulated in SCLC and can, therefore, be leveraged for selective tumour targeting with the antibody–drug conjugate rovalpituzumab tesirine (Rova-T). Inhibitors of the histone-lysine N-methyltransferase EZH2 (also known as enhancer of zeste homologue 2), the enzymatic histone-lysine N-methyltransferase subunit of the polycomb repressive complex 2 (PRC2) chromatin-remodelling machinery, can prevent chemoresistance and cell proliferation by counteracting epigenetic gene silencing, in particular, of schlafen family member 11 (SLFN11) — a protein that negatively regulates homologous recombination DNA repair. Poly [ADP-ribose] polymerase (PARP) inhibitors prevent the activation of DNA-repair proteins by PARP1 and trap this enzyme on DNA, which causes further DNA damage that can eventually result in cell death. APC, antigen-presenting cell; ASCL1, achaetescute homologue 1 (also known as ASH-1); Chk1/2, checkpoint kinase 1/2; E2F1, transcription factor E2F1 (also known as retinoblastoma-associated protein 1); PAR, poly-ADP-ribosylation.