Signal pathways and precision therapy of small-cell lung cancer

Abstract

Small-cell lung cancer (SCLC) encounters up 15% of all lung cancers, and is characterized by a high rate of proliferation, a tendency for early metastasis and generally poor prognosis. Most of the patients present with distant metastatic disease at the time of clinical diagnosis, and only one-third are eligible for potentially curative treatment. Recently, investigations into the genomic make-up of SCLC show extensive chromosomal rearrangements, high mutational burden and loss-of-function mutations of several tumor suppressor genes. Although the clinical development of new treatments for SCLC has been limited in recent years, a better understanding of oncogenic driver alterations has found potential novel targets that might be suitable for therapeutic approaches. Currently, there are six types of potential treatable signaling pathways in SCLC, including signaling pathways targeting the cell cycle and DNA repair, tumor development, cell metabolism, epigenetic regulation, tumor immunity and angiogenesis. At this point, however, there is still a lack of understanding of their role in SCLC tumor biology and the promotion of cancer growth. Importantly optimizing drug targets, improving drug pharmacology, and identifying potential biomarkers are the main focus and further efforts are required to recognize patients who benefit most from novel therapies in development. This review will focus on the current learning on the signaling pathways, the status of immunotherapy, and targeted therapy in SCLC.

Fig. 1

Six main representative therapeutically tractable targets in small-cell lung cancer (SCLC). a Cell cycle and DNA damage repair pathways. PARP poly (ADP)-ribose polymerase, AURKA Aurora A kinase, CHK1 checkpoint kinase 1, ATR Ataxia telangiectasia and rad3 related, RS replication stress. b Metabolism and angiogenesis signaling pathways. PKA protein kinase A. c Developmental and epigenetic regulators. NE neuroendocrine, TUG taurine upregulated gene1. d Antitumour immunity. PD-1 programmed death-1, PD-L1 programmed death ligand-1, CTLA-4 cytotoxic T-lymphocyte-associated antigen 4, TIGIT T-cell immunoreceptor with immunoglobulin and ITIM domains

Fig. 2

Timeline of key studies of immune checkpoint inhibitors in SCLC. This timeline describes some key studies using immune checkpoint inhibitors in patients with SCLC. NR not reported, ORR objective response rate, PFS progression-free survival, OS overall survival

Fig. 3

Potential combination strategies of ICIs in order to overcome resistance based on the immune phenotype. Antitumor immunity can be classified into three main phenotypes: the immuno-desert tumor (a), the immuno-excluded tumor (b) and the immuno-inflamed tumor (c). Each of this phenotype is associated with multiple mechanisms of resistance to immunotherapy. In order to overcome resistance to single-agent CPI, combination strategies have been suggested. The most promising ones comprise the combination with another ICIs, cytotoxic chemotherapy, radiation, antiangiogenesis or targeted therapies