Targeting Oncogenic RET Kinase by Simultaneously Inhibiting Kinase Activity and Degrading the Protein.

The rearranged-during-transfection (RET) kinase is a validated target for the treatment of RET-altered cancers. Currently approved RET-selective kinase inhibitors, selpercatinib (LOXO-292) and pralsetinib (BLU-667), increase the oncogenic RET protein level upon treatment, which may affect their efficacy. We seek to reduce the oncogenic RET protein level and RET kinase activity simultaneously.

Progress and challenges in RET-targeted cancer therapy.

The rearranged during transfection (RET) is a receptor protein tyrosine kinase. Oncogenic RET fusions or mutations are found most often in non-small cell lung cancer (NSCLC) and in thyroid cancer, but also increasingly in various types of cancers at low rates. In the last few years, two potent and selective RET protein tyrosine kinase inhibitors (TKIs), pralsetinib (BLU-667) and selpercatinib (LOXO-292, LY3527723) were developed and received regulatory approval.

Targeting RET Solvent-Front Mutants with Alkynyl Nicotinamide-Based Inhibitors.

Selpercatinib (LOXO292) and pralsetinib (BLU667) are RET protein tyrosine kinase inhibitors (TKIs) recently approved for treating RET-altered cancers. However, RET mutations that confer selpercatinib/pralsetinib resistance have been identified, necessitating development of next-generation RET TKIs. While acquired RET G810C/R/S/V mutations were reported in selpercatinib-treated patients, it was unclear whether all of these and other potential G810 mutants are resistant to selpercatinib and pralsetinib.

The heterogeneous transition state of resistance to RET kinase inhibitors converges on ERK1/2-driven Aurora A/B kinases.

Aim: While most patients with RET-altered cancer responded to the RET protein tyrosine kinase inhibitors (TKIs) pralsetinib (BLU667) and selpercatinib (LOXO292), few achieved a complete response. Heterogeneity in residual tumors makes it difficult to target their diverse genetic alterations individually. The aim of this study is to characterize the cancer cells that persist under continuous RET TKI treatment and identify the shared vulnerability of these cells.

The origin of exosomal miR-1246 in human cancer cells.

miR-1246 is considered an oncomiR in various cancer types. However, the origin and biogenesis of miR-1246 remain controversial which often leads to misinterpretation of its detection and biological function, and inevitably masking its mechanisms of action. Using next generation small RNA sequencing, CRISPR-Cas9 knockout, siRNA knockdown and the poly-A tailing SYBR qRT-PCR, we examined the biogenesis of exosomal miR-1246 in human cancer cell model systems.