Molecular profiles of small cell lung cancer subtypes: therapeutic implications

Abstract

Small cell lung cancer (SCLC; accounting for approximately 13%-15% of all lung cancers) is an exceptionally lethal malignancy characterized by rapid doubling time and high propensity to metastasize. In contrast to the increasingly personalized therapies in other types of lung cancer, SCLC is still regarded as a homogeneous disease and the prognosis of SCLC patients remains poor. Recently, however, substantial progress has been made in our understanding of SCLC biology. Advances in genomics and development of new preclinical models have facilitated insights into the intratumoral heterogeneity and specific genetic alterations of this disease. This worldwide resurgence of studies on SCLC has ultimately led to the development of novel subtype-specific classifications primarily based on the neuroendocrine features and distinct molecular profiles of SCLC. Importantly, these biologically distinct subtypes might define unique therapeutic vulnerabilities. Herein, we summarize the current knowledge on the molecular profiles of SCLC subtypes with a focus on their potential clinical implications.

Keywords: heterogeneity; molecular profile; neuroendocrine; small cell lung cancer.

Graphical abstract

Figure 1

Timeline of relevant therapeutic advances for small cell lung cancer (SCLC) Initial therapeutic strategies for SCLC included surgery or radiotherapy alone. However, given the aggressive behavior and high metastatic potential of SCLC, systemic therapy with cytotoxic agents has rapidly become the cornerstone of management. In the 1940s, alkylating agents (such as nitrogen mustard) were used for the treatment of all bronchogenic carcinomas (including SCLC), resulting in tumor regression in more than 50% of patients. Yet, at that time, the true nature of SCLC was widely unknown, and all lung carcinomas were treated similarly. The first chemotherapeutic agent to show a statistically significant survival benefit for selected SCLC patients was cyclophosphamide, which doubled the survival when compared to best supportive care alone , , . Despite the encouraging results with single-agent therapy, it became obvious early in the 1970s that combination therapy produces superior survival outcomes when compared to single-agent treatment , . Therefore, during the late 1970s and early 1980s, cyclophosphamide was used in combination with other cytotoxic agents such as doxorubicin and vincristine (CAV). The basis of the currently used platinum-based combination chemotherapy (CHT) was defined during the mid-1980s when Evans et al. showed a clear survival benefit for patients treated with cisplatin plus etoposide. Since then, there have been no relevant advances in the standard-of-care CHT regimens, and the backbone for current combination strategies are still the platinum compounds. In more recent years, targeted therapy and immunotherapy have also been actively tested, leading to the approval of several immune-checkpoint inhibitors such as atezolizumab, pembrolizumab, and nivolumab.

Figure 2

Tumor heterogeneity in SCLC with regard to neuroendocrine differentiation, molecular subtypes, and gene expression profile Neuroendocrine (NE) differentiation can be defined by the expression pattern of different NE markers, including chromogranin A, synaptophysin, neural cell adhesion molecule 1, and gastrin-releasing peptide. However, a minority of SCLCs are negative for all standard NE markers. Additionally, SCLC can be subclassified according to the relative expression of four key transcriptional regulators: achaete-scute homolog 1 (ASCL1; also known as ASH1), neurogenic differentiation factor 1 (NEUROD1), yes-associated protein 1 (YAP1), and POU class 2 homeobox 3 (POU2F3). Various genetic alterations, biological properties, and thus potential therapeutic vulnerabilities are associated with these molecular subsets.

Figure 3

Potential novel therapeutic approaches in SCLC Subtype-specific potential therapeutic targets for SCLC-A, SCLC-N, SCLC-P, and SCLC-Y subtypes are highlighted in yellow (BCL2 and DLL3), gray (c-MYC and AURKA), red (PARP and IGF-1R), and green (CDK4/6 and PD-L1), respectively. The association between the aforementioned molecular subtypes and the potentially targetable molecules highlighted in blue (PDGFR, VEGFR, FGFR, CTLA-4 and PD-1), is currently unknown. The figure was created with BioRender.