Selected Articles from This Issue

Abstract

PRMT5 over-expression occurs in multiple cancer types, including non-small cell lung cancer (NSCLC). PRMT5 inhibition generates intron retention and exon skipping, resulting in promotion of apoptosis. Mutations conferring drug resistance have challenged previous SAM-cooperative PRMT5 inhibitors entering clinical trials. In this First Disclosure, Jensen-Pergakes and colleagues identify PF-06939999, a SAM-competitive PRMT5 inhibitor, through a structure-based design. Analysis of acquired resistance to SAM-cooperative and SAM-competitive PRMT5 inhibition suggested the latter may be less susceptible to complete drug resistance. PF-06939999 demonstrated anti-proliferative activity in NSCLC tumors with multiple pathways downregulated. Their results support the clinical development of PF-06939999 in splicing dysregulated NSCLC.Transforming growth factor β (TGFβ) signaling suppresses anti-tumor immunity, promotes tumor invasion, and modulates tumor response to chemotherapy. Therefore, inhibitors of TGFβ and associated biomarkers to identify candidates for inhibition are highly desired. In this review article, Liu and colleagues outline the successes and limitations in characterizing the consequences of TGFβ inhibition in various cancer types. Due to its pleiotropic nature, suppression of the pathway in preclinical studies has demonstrated an ability to either promote or restrict cancer therapy. Therefore, focus is also placed on the predictive value of TGFβ biomarkers in cancer therapy.Achieving 5-year survival in pancreatic ductal adenocarcinoma (PDA) remains elusive due to late diagnosis and therap. resistance. The leading cause of death in pancreatic cancer is metastasis, driven in part by the receptor tyrosine kinase AXL and its role in epithelial-mesenchymal transition (EMT). Zhang and colleagues outline the anti-tumor and anti-metastatic effects of the AXL inhibitor TP-0903. TP-0903 extended survival both alone and in combination with gemcitabine in a genetically engineered mouse model of PDA. In a refractory syngenic model, TP-0903 showed effectiveness in combination with gemcitabine and/or anti-PD-1 therapy. Their results support the ongoing clinical study of TP-0903 in advanced solid tumors (NCT02729298).Rhabdomyosarcoma (RMS) is the most common soft tissue cancer in children. RAS mutations are frequent in PAX-fusion negative (FN)-RMS and contribute to therapy response. In this study, Garcia and colleagues validate the contribution of RAS mutations to FN-RMS and demonstrate its contribution to MEK inhibitor (trametinib) resistance. They demonstrate that MEK inhibition alone was insufficient to restrict the progression of RAS Q61X-mutant tumors due to MAPK reactivation. Furthermore, a combination of any two inhibitors between MEK, pan-RAF, and ERK inhibitors generated apoptosis in FN-RMS cell lines and enhanced in vivo efficacy in xenografts compared to monotherapy.