Origins, genetic landscape, and emerging therapies of small cell lung cancer

Abstract

Lung cancer is the leading cause of cancer deaths, with small cell lung cancer (SCLC) representing the most aggressive subtype. Standard treatments have not changed in decades, and the 5-year survival rate has remained <7%. Genomic analyses have identified key driver mutations of SCLC that were subsequently validated in animal models of SCLC. To provide better treatment options, a deeper understanding of the cellular and molecular mechanisms underlying SCLC initiation, progression, metastasis, and acquisition of resistance is required. In this review, we describe the genetic landscape of SCLC, features of the cell of origin, and targeted therapeutic approaches.

Glucocorticoid receptors in lung cancer: new perspectives

“…Bronchioalveolar stem cells are postulated to play a role in NSCLC tumourigenesis, while a rare population of neuroendocrine cells or less differentiated cells are thought to be the progenitor cells for SCLC. However, the cell/s of origin for these different lung cancers have not been definitively described with recent studies revealing remarkable plasticity in the regenerative powers of various lung cell types, further complicating the matter (Semenova et al 2015).…”

Circulating tumor cell interactions with macrophages: implications for biology and treatment

“…This tumor responds initially excellent to platinum-based chemotherapy in most cases but invariably relapses rapidly with a dismal prognosis (7,33). Contrary to increasing 5-year survival rates for other solid cancers, therapeutic options for SCLC have remained unchanged for the last decades, with minor improvement in outcomes (34).…”

“…SCLC is an aggressive neuroendocrine malignancy characterized by aggressive growth and early development of metastases (7,32). This tumor responds initially excellent to platinum-based chemotherapy in most cases but invariably relapses rapidly with a dismal prognosis (7,33).…”

“…Small cell lung cancer (SCLC) accounts for approximately 15% of lung cancers and represents an aggressive tumor with high numbers of CTCs which are involved in early dissemination (7). The unique properties of CTCs of ED-SCLC allowed us to expand six cell lines from blood samples of patients with metastatic disease in vitro (BHGc7, 10,16,26,27 and UHGc5) and to study their cell biologic characteristics and interaction with normal cell populations of the tumor microenvironment (8).…”

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

“…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). Although it was reported that somatic genomic rearrangements of TP73 contribute to SCLC tumorigenesis (5), druggable gene aberrations are rarely identified.…”