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]. As opposed to SCLC, oncogenic drivers with sensitivity to targeted therapies have been discovered in NSCLC. Tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) rearrangements, or other oncogenic abnormalities have brought remarkable improvements in the outcome of oncogenic-driven NSCLC patients [2]. Immunotherapy with anti-programmed death-(ligand) 1 (PD-(L)1) immune checkpoint inhibitors (ICIs) has also significantly improved the survival of NSCLC patients without oncogenic drivers [3,4,5,6,7,8,9]. Clinically, SCLC is the most aggressive type of lung cancer, being characterized by a high growth rate, a fast doubling time, and a tendency for early metastasis, with two-thirds of the patients diagnosed with an extensive stage (ES) disease [10,11]. While a good initial response to chemotherapy and/or radiation therapy is observed in most patients, they typically recur or progress rapidly after the primary treatment, with a median overall survival (OS) of 24–38 months in limited stage (LS) [12,13] and 7–10 months in ES [14], and a five-year OS as low as 5% [1].

Despite improvements in the understanding of the molecular steps that lead to SCLC development and progression these last years, there are still no effective targeted therapies in SCLC. Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate (pyrrolobenzodiazepine (PBD)-dimer cytotoxic) that is directed against Delta-like 3 (DLL3), an inhibitory NOTCH ligand, which has been shown to be overexpressed on the surface of SCLC cells [15]. 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]. After four decades, 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]. At relapse or progression after a first-line treatment, a rechallenge with platinum and etoposide is proposed to tumors that are considered to be sensitive to platinum (relapse or progression within 60 or 90 days of completion of chemotherapy) [18], while a second-line chemotherapy with topotecan is proposed to tumors platinum-refractory (relapse or progression before three to six months). However, the response rates are poor and OS ranges from 1.2 months to 7.6 months based on systematic reviews of real-world data 15 [19]. These disappointing results highlight the need for novel therapies.

Focal adhesion kinase (FAK) is a 125 kDa non-receptor protein tyrosine kinase that is known to be overexpressed and activated in several cancers, including SCLC [20,21,22,23,24,25,26,27,28]. Unlike receptor tyrosine kinases (RTKs), such as epidermal growth factor receptor (EGFR), non-RTKs, such as FAK, are cytoplasmic enzymes that lack transmembrane and extracellular domains [29]. FAK localizes to focal adhesions and it is triggered off by extracellular signals, such as integrin-mediated adhesion and some growth factors [30]. Therefore, FAK plays a central role in the interaction between cells, including cancer cells and their microenvironment. The FAK structure includes an NH2-terminal Protein4.1-ezrin-radixin-moesin (FERM) domain, a central kinase domain, two proline-rich motifs, and a COOH-terminal focal adhesion targeting (FAT) domain. FAK is maintained in an inactive state by the binding of the FERM domain to the kinase domain, which blocks access to the catalytic site and sequesters the activation loop, as well as the key autophosphorylation site tyrosine 397 (Tyr397) (Figure 1). The engagement of integrins with the extracellular matrix (ECM) or growth factors leads to signals that displace the FERM domain, resulting in rapid autophosphorylation of Tyr397, which is a critical event in signal transduction by FAK [30,31]. Tyr397 phosphorylation provides a binding site that recruits and activates Src through the SH2 domains of Src family kinases. The FAK-Src complex therefore maintains Src and FAK in their activated states, creating a functional kinase complex [32].

Based on FAK overexpression and/or increased activity in cancer and its known function in multiple biological processes that play a role in the development and progression of cancers, such as crosstalk between cell and his microenvironment, cell growth, survival, adhesion, spreading, migration, invasion, angiogenesis, DNA damage repair, radioresistance, and regulation of cancer stem cells, it has been suggested that increased the expression and/or activity of FAK may have a critical role in cancer development and progression [33]. Therefore, FAK is a potential target for anti-cancer therapy, especially in SCLC, being known to be a highly invasive cancer. Small-molecule inhibitors targeting the FAK kinase domain and preventing FAK activation (Tyr397 autophosphorylation) have been developed. Phase I trials with GSK2256098 [34,35,36], VS-6062 [37], defactinib (VS-6063) [38,39,40], or BI853520 [41,42,43] have shown an acceptable safety profile and favorable pharmacokinetics. Most frequent treatment-related adverse events included digestive disorders (nausea, diarrhea, vomiting), headaches, reversible proteinuria, and unconjugated hyperbilirubinemia [34,35,36,37,38,39,40,41,42]. With GSK2256098, the best response of stable disease was observed in 37% of glioblastoma (three patients, median PFS 5, seven weeks) [36] and in 45% of advanced solid cancers (28 patients) [35]. With VS-6062, 34% of patients (31 patients) with advanced solid tumors exhibited stable disease at six weeks, including one case of SCLC for ≥6 cycles cycles [37]. VS-6063 led to the stabilization of advanced solid tumors in 43% of Caucasian patients (six cases) after six weeks of treatment [38] and in 33% of Asian patients (three cases) during more than 24 weeks (median PFS of 63 days) [40]. Recently, the combination of the FAK inhibitor GSK2256098 and the MEK inhibitor trametinib in recurrent advanced pancreatic ductal adenocarcinoma did not provide significant clinical activity in a phase II trial (PFS of 1.6 month and OS of 3.6 months) [44]. In malignant pleural mesothelioma, defactinib in maintenance after first-line chemotherapy in a phase II trial did not provide any benefit either (PFS of 4.1 months with defactinib vs 4.0 months with placebo, and OS of 12.7 months with defactinib vs. 13.6 months with placebo) [45]. Preoperative administration of defactinib in the ongoing phase II clinical trial NCT02004028 appears promising, with therapeutic activity (13% objective partial response, 67% stable disease, 17% tumor progression) and beneficial modification of the tumoral microenvironment [46]. Several clinical trials with defactinib associated with immunotherapy (NCT02758587, NCT03727880, NCT02943317), RAK/MEK inhibitor (NCT03875820), or chemotherapy (NCT02546531) are ongoing, with some of them being open to SCLC inclusion (Table 1) [34,35,36,37,39,40,41,42,43,44,45,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61]. Other small-molecules targeting the protein-protein interactions between FAK and other proteins, such as VEGFR-3, called scaffolding inhibitors, have been developed and shown to induce antitumoral effects in preclinical studies. Further research is needed to find predictive biomarkers of response to FAK TKI alone or, probably more promising, in association with another drug.