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Review
. 2021 Apr 1;11(4):a038240.
doi: 10.1101/cshperspect.a038240.

Advances in Small-Cell Lung Cancer (SCLC) Translational Research

Benjamin J Drapkin  1 , Charles M Rudin  2
Affiliations
Review

Advances in Small-Cell Lung Cancer (SCLC) Translational Research

Benjamin J Drapkin et al. Cold Spring Harb Perspect Med. .

Abstract

Over the past several years, we have witnessed a resurgence of interest in the biology and therapeutic vulnerabilities of small-cell lung cancer (SCLC). This has been driven in part through the development of a more extensive array of representative models of disease, including a diverse variety of genetically engineered mouse models and human tumor xenografts. Herein, we review recent progress in SCLC model development, and consider some of the particularly active avenues of translational research in SCLC, including interrogation of intratumoral heterogeneity, insights into the cell of origin and oncogenic drivers, mechanisms of chemoresistance, and new therapeutic opportunities including biomarker-directed targeted therapies and immunotherapies. Whereas SCLC remains a highly lethal disease, these new avenues of translational research, bringing together mechanism-based preclinical and clinical research, offer new hope for patients with SCLC.

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Figures

Figure 1.
Figure 1.
Frequently used in vivo models of small-cell lung cancer (SCLC). Cell-line-derived xenografts (CDXs) have been a mainstay of SCLC research for many years. These have advantages including speed, number of available models, and ease of use. Genetically engineered mouse models have greatly expanded in number and complexity. These have advantages including immunocompetence, in situ oncogenesis, and ability to definitively test the role of individual drivers. The number of available patient-derived xenograft (PDX) and CDX models is also rapidly increasing in laboratories around the world. These have advantages including genetic and epigenetic proximity to human disease, heterogeneity, and links to individual patient outcomes. An additional advantage of CDX is the broad availability of blood as a source for model generation.
Figure 2.
Figure 2.
Cell of origin versus destination phenotype. Multiple cells of origin have been implicated as contributing to small-cell lung cancer (SCLC). As described in detail in the text, current models point to pulmonary neuroendocrine cells (PNECs) as a primary cell of origin; recent data also implicates a second cell, the tuft cell, as a putative progenitor of the POU2F3-driven subtype of SCLC. Lung adenocarcinoma can transdifferentiate to an SCLC phenotype through lineage plasticity under targeted therapy selection, and what appears to be an analogous pathway to small-cell neuroendocrine cancers has been defined for extrapulmonary adenocarcinomas, most notably prostate cancer.
Figure 3.
Figure 3.
DNA damage checkpoints and vulnerabilities in small-cell lung cancer (SCLC). The universal inactivation of the tumor-suppressor genes TP53 and RB1 in SCLC disrupts several key cell-cycle checkpoints, affecting cell-cycle entry from G1 to S, response to DNA damage in S phase, and commitment to mitotic entry in G2. The loss of these checkpoints may increase dependence on remaining checkpoint pathways, creating a synthetic vulnerability in SCLC to inhibitors of DNA damage repair pathways. Critical factors lost in SCLC are indicated in red, additional notable factors controlling cell-cycle progression are indicated in blue, and targeted therapies being explored in SCLC are boxed in black.
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