Abstract
Small-cell lung cancer (SCLC) represents 15% of all lung cancers and it is clinically the most aggressive type, being characterized by a tendency for early metastasis, with two-thirds of the patients diagnosed with an extensive stage (ES) disease and a five-year overall survival (OS) as low as 5%. There are still no effective targeted therapies in SCLC despite improved understanding of the molecular steps leading to SCLC development and progression these last years. After four decades, the only modest improvement in OS of patients suffering from ES-SCLC has recently been shown in a trial combining atezolizumab, an anti-PD-L1 immune checkpoint inhibitor, with carboplatin and etoposide, chemotherapy agents. This highlights the need to pursue research efforts in this field. Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase that is overexpressed and activated in several cancers, including SCLC, and contributing to cancer progression and metastasis through its important role in cell proliferation, survival, adhesion, spreading, migration, and invasion. FAK also plays a role in tumor immune evasion, epithelial-mesenchymal transition, DNA damage repair, radioresistance, and regulation of cancer stem cells. FAK is of particular interest in SCLC, being known for its aggressiveness. The inhibition of FAK in SCLC cell lines demonstrated significative decrease in cell proliferation, invasion, and migration, and induced cell cycle arrest and apoptosis. In this review, we will focus on the role of FAK in cancer cells and their microenvironment, and its potential as a therapeutic target in SCLC.
Highlights
Lung cancer, which arises from lung epithelial cells, is histologically divided into two main types: small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), which represent 15% and 85% of the cases, respectively [1]
In a more recent study, multiplex immunofluorescence staining in 105 SCLC and 95 nonNSCLC patients, as well as 37 healthy donors, revealed that Focal adhesion kinase (FAK) and phospho-FAK (Y397) expression was significantly higher in lung cancer than in normal lung, and significantly higher in SCLC when compared to NSCLC tissues (p < 0.01)
In SCLC the association of the PARP inhibitor olaparib and the anti-PD-L1 immune checkpoint inhibitors (ICIs) durvalumab in a phase II trial did not meet efficacy criteria, but revealed that responses were only observed in tumors with an inflamed phenotype on tissue biopsies at baseline, which suggests that the tumor microenvironment inflammation phenotype is a potential predictive biomarker [212]
Summary
Lung cancer, which arises from lung epithelial cells, is histologically divided into two main types: small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), which represent 15% and 85% of the cases, respectively [1]. Despite encouraging preclinical and early clinical results, targeted therapy with Rova-T underperformed in the phase II TRINITY trial, including pretreated SCLC patients with high levels of DLL3 on tumor cell surface [15,16]. The only modest improvement in the OS of patients suffering from ES-SCLC has recently been shown in a trial combining atezolizumab, an anti-PD-L1 ICI, with carboplatin and etoposide, chemotherapy agents [17] In this trial, the OS was 10.3 months in the chemotherapy alone arm, while it was. 12.3 months in the chemotherapy plus immunotherapy arm Based on this positive trial, atezolizumab that is associated to carboplatin an etoposide recently became the new standard of care in the first-line treatment of ES-SCLC [17]. Solid tumors (ovarian, pancreatic, meningioma, glioblastoma, Prostate, malignant breast pleural mesothelioma)
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