Targeted Therapies and Biomarkers in Small Cell Lung Cancer

Abstract

Small cell lung cancer (SCLC) is an aggressive malignancy characterized by rapid growth, early metastasis, and acquired therapeutic resistance. A majority of patients with SCLC have extensive-stage (ES) disease, defined as the presence of metastatic disease outside the hemithorax at first diagnosis. SCLC has been considered "a graveyard for drug development," with chemotherapy remaining the standard treatment for first-and second-line management until quite recently. In contrast to NSCLC, identifying therapeutic targets in SCLC has been challenging, partly because driver mutations are primarily loss of function, involving the tumor suppressor genes RB1 and TP53 or currently untargetable (e.g., amplification of MYC family members). Recent gene expression profiling of SCLC cells lines, patient samples and representative murine models, have led to a proposed delineation of four major subtypes for SCLC distinguished by differential expression of four key transcriptional regulators (ASCL1, NEUROD1, POU2F3, and YAP1). Our understanding of the biology of SCLC has indeed significantly improved recently due to the continued efforts of the dedicated investigators in this field, but the therapeutic options remain dismal. While recent results from immunotherapy trials are encouraging, most patients demonstrate either primary or rapid acquired resistance to current regimens, highlighting the clear need to improve the effectiveness and expand the scope of current therapeutic strategies. In this opinion article, we will discuss recent developments in the treatment of SCLC, focused on current understanding of the signaling pathways, the role of immunotherapy and targeted therapy, and emerging biomarkers of response to therapy in SCLC.

Gene Amplification-Associated Overexpression of the Selenoprotein tRNA Enzyme TRIT1 Confers Sensitivity to Arsenic Trioxide in Small-Cell Lung Cancer

“…Since there are few therapeutic options for treating this malignancy and little evidence that they have improved outcomes in recent years [ 30 , 31 ], we wondered whether the copy number gain of TRIT1 is associated with an increased sensitivity to antitumor drugs. Arsenic trioxide could be one such candidate compound [ 32 , 33 ].…”

“…Small-cell lung cancer is an aggressive malignancy in which a majority of patients at first diagnosis already show metastatic disease outside the hemithorax [ 30 , 31 ]. It accounts for approximately 13% of all new lung cancer diagnoses, but in contrast to non-small-cell lung cancer the implementation of targeted treatments in small-cell lung cancer has been limited, with chemotherapy having been the standard therapy for first- and second-line clinical management for several decades [ 30 , 31 ]. One of the main issues is the appearance of chemoresistance at recurrence, a type of sample that was not included in our study.…”

“…In addition to expanding the role of the epitranscriptome in tumorigenesis [ 1 , 2 ], illustrated here by the described tRNA modification, another aspect of the TRIT1 gene amplification in small-cell lung cancer might have an additional impact on the treatment of this malignancy. The first significant improvement in the clinical outcome of small-cell lung cancer in several decades is the recent addition of immune checkpoint blockade to the therapeutic arsenal against the disease [ 30 , 31 ]. This led the US Food and Drug Administration to approve the use of the anti-PD-L1 inhibitor atezolizumab in combination with carboplatin plus etoposide chemotherapy to treat extensive-stage disease [ 43 ].…”

Curcumin-Induced Global Profiling of Transcriptomes in Small Cell Lung Cancer Cells

“…However, SCLC is more aggressive and has a greater tendency to spread to other organs in the body. Although advancements of chemotherapy and radiotherapy have improved the outcome of SCLC, its prognosis is still discouraging ( Taniguchi et al, 2020 ). Therefore, more efforts are required to find new alternative strategies and enhance the effectiveness of integrated treatment strategies in SCLC.…”

Editorial: Update on the Biology, Management, and Treatment of Small Cell Lung Cancer

“…The article summarizes our current understanding of the various signaling pathways and targets of therapeutic significance in SCLC. The authors have also described emerging therapeutic targets and biomarkers of targeted therapy for SCLC ( 12 ).…”