Targeting SWI/SNF mutant cancers with tyrosine kinase inhibitor therapy

The SWI/SNF chromatin remodeling complex orchestrates the repositioning of nucleosomes and is necessary for the regulation of multiple fundamental processes including DNA replication and repair, gene expression, and cell division [1]. Genes encoding subunits of the SWI/SNF complex are potent tumor suppressors and inactivating mutations in these genes are found in ~20% of cancers [2,3]. This class of cancers is almost universally fatal and there currently are no effective treatments, in part because the SWI/SNF complex is deemed undruggable. For an overview of the fundamentals of SWI/ SNF structure and function, readers are directed to recent excellent reviews [1,4]. Emerging evidence indicates that exploiting tyrosine kinase dependencies arising from SWI/ SNF subunit loss may be an effective strategy to overcome cancers driven by these tumor suppressor genes. Specifically, recent preclinical data suggest that tyrosine kinase inhibitors (TKIs) have utility in the treatment of this class of cancers. This editorial summarizes the current knowledge of tyrosine kinase dependencies in SWI/SNF mutant cancers and discusses outstanding questions and barriers that need to be overcome in order to translate these preclinical results into patient benefit. SMARCB1 is a core subunit of the SWI/SNF complex located at the 22q11 chromosomal region. It is capable of forming two distinct and mutually exclusive complexes containing either the SMARCA2 or the SMARCA4 ATPdependent helicases [4]. Loss of SMARCB1 is a driver in a number of cancer types, including rhabdoid tumors (RTs), epithelioid sarcomas, renal medullary carcinoma, epithelioid malignant peripheral nerve sheath tumors, meningiomas and extraskeletal myxoid chondrosarcomas [5]. Tyrosine kinase dependencies associated with SMARCB1 deficiency have been most well studied in RTs and include oncogene addiction to the epidermal growth factor receptor (EGFR) and Human EGFR 2 (HER2) [6–8]. Screening three RT cell lines across a panel of 129 small molecular inhibitors, Singh et al. showed that targeting EGFR-HER2 signaling using the EGFR-HER2 TKI lapatinib was effective in blocking tumor cell migration and inducing apoptosis in vitro [8]. Similarly, Kuwahara et al. found that RT cell lines displayed high levels of EGFR expression and inhibiting EGFR phosphorylation with the EGFR TKI gefitinib was capable of reducing cell growth both in vitro and in vivo [7]. These findings are consistent with a recent phosphoproteomic analysis of Smarcb1-deficient RT murine cells derived from a genetically engineered mouse model which showed that Smarcb1 loss led to the upregulation of EGFR phosphorylation and activation of the AKT pro-survival pathway [6]. Interestingly, in this study, lapatinib suppressed EGFR phosphorylation while gefitinib had the opposite effect of elevating receptor activation, although the mechanistic basis of this counterintuitive finding was not pursued. In addition to EGFR and HER2, other receptor tyrosine kinases (RTKs) such as fibroblast growth factor receptors (FGFRs), insulin-like growth factor 1 receptor (IGF-1R), and the c-MET receptor are also active in SMARCB1-deficient cancers. Wohrle et al. found that RT cell lines express high levels of FGFRs, including FGFR1 and FGFR2 [9]. They showed that ectopic expression of SMARCB1 in these cell lines led to the downregulation of FGFR protein expression and that the mechanism involved direct binding of SMARCB1 to the FGFR2 promoter locus. Importantly, the use of the FGFR inhibitor NVP-BGJ398 was capable of blocking FGFR signaling through the ERK pathway and inhibiting RT cell growth in vitro and in vivo. Wong et al. recently found that dual inhibition of platelet-derived growth factor receptor alpha (PDGFRα) and FGFR1 induces synergistic cytotoxicity in RT cells [10]. D’Cunja et al. demonstrated that IGF-1R was expressed in RT patient specimens while its cognate ligands IGF-1 and IGF-II were highly expressed in RT cell lines [11]. This finding suggests that an autocrine/ paracrine loop may exist in RT cells where high levels of ligand lead to the activation of IGF-1R ultimately promoting tumor growth. Given that the authors did not perform SMARCB1 reexpression experiments, it remains unclear if SMARCB1 directly regulates IGF-1R and/or ligand expression. However, silencing of IGF-1R levels using antisense oligonucleotides was capable of suppressing RT cell proliferation and inducing apoptosis. In addition, IGF-1R downregulation sensitized RT cells to chemotherapy in the form of doxorubicin and cisplatin. Brenca et al. published a short report describing the expression and coactivation of EGFR and c-Met in the VAESBJ epithelioid cell line which lacks SMARCB1 [12]. These receptors activated the AKT and ERK pathways and combined inhibition of both RTKs using two