Highlights of This Issue

The rarity of RET oncofusions in lung cancer impairs the pace of clinical studies in this subtype. Huang and colleagues established a transgenic KIF5B–RET fusion lung cancer mouse model that can develop invasive lung adenocarcinoma with fibrotic desmoplasia. The authors also identified RET^V804L gatekeeper and vandetanib-resistant RET^G810A mutations in cultured cells with increasing concentrations of RET inhibitors. Ponatinib was identified as the most potent RET inhibitor, displayed hyperactivity to RET^G810A, and caused lung tumor regression in the animals. These studies established preclinical models that can rapidly evaluate efficacy of RET inhibitors, discover resistance mechanisms, and identify approaches to thwart resistance.

Therapeutically targeting intracellular kinases is biologically attractive but fundamentally challenging. Interpreting drug behavior in cellular and animal models is confounded by redundant enzymatic activities, common substrates, and cell-specific signaling networks. To better understand clinical characteristics, cyclin-dependent kinase drugs (abemaciclib, dinaciclib, palbociclib, ribociclib) were profiled using cellular (untransformed, tumorigenic), biophysical, and structural approaches. CDK–drug co-crystal structures coupled with biochemical analyses reveal a unique hinge architecture that enables kinome selectivity and the extent of CDK family engagement is derived from other ATP binding pocket interactions. Together, these findings provide insight into drug pharmacology and a framework for rational drug design.

A liposome-based platform for the co-delivery of the 3rd generation P-gp inhibitor tariquidar and paclitaxel was developed to overcome Taxol resistance in ovarian cancer cells. Using several functional assays and imaging approaches, Zhang, Sriraman, and colleagues showed that the dual drug-loaded liposomes inhibited cell viability, blocked proliferation, and caused G₂–M arrest in vitro. In a xenograft model of Taxol resistance ovarian cancer, the liposomes significantly impeded tumor growth through the induction of apoptosis and reduction of proliferation. This novel nanomedicine has potential for clinical testing in ovarian cancer patients with P-gp–overexpressing tumors.

The expression of small heterodimer partner (SHP, NROB2) is downregulated in metastatic HCC and is negatively associated with patient survival in several types of aggressive and highly metastatic human cancers. In this study, Yang and colleagues performed small molecule microarrays and discovered a novel activator of SHP, namely DSHN. DSHN transcriptionally activated Shp mRNA, but also stabilized SHP protein by preventing its ubiquitination and degradation. In vivo and in vitro evidence indicated that DSHN inhibited HCC metastasis via SHP-mediated repression of Ccl2 signaling. This study highlights the potential use of SHP as a therapeutically tractable gene in preclinical and translational studies.