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...

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