Targeting RET alterations in cancer: Recent progress and future directions

Genomic alterations in the receptor tyrosine kinase RET represent actionable driver events in several cancer types. Activation of the kinase domain by point mutations represents a pathognomonic event in medullary thyroid cancer, while RET fusions are critical driver events in a sizable subset of differentiated thyroid cancer and a smaller percentage of lung cancer. Early trials with multi-kinase inhibitors yielded modest improvement in outcomes for RET-driven cancers. In recent years, highly selective RET inhibitors entered clinical trials and demonstrated remarkable response rates, resulting in accelerated approval for selpercatinib and pralsetinib in 2020. An important mechanism of eventual resistance to RET inhibitors is the emergence of secondary drug resistance mutations, particularly in the solvent front, and several promising compounds are in development to overcome these mutations. Mechanisms of acquired resistance that bypass RET signaling altogether have also been discovered, suggesting that combinatorial drug strategies may be necessary for some patients.

Automated summary

Genomic alterations in the RET receptor tyrosine kinase are actionable driver events in various cancers. RET point mutations and fusions are implicated in medullary thyroid cancer, differentiated thyroid cancer, and lung cancer. Recent clinical trials have shown promising response rates with highly selective RET inhibitors, leading to accelerated approval of selpercatinib and pralsetinib in 2020. Resistance to these inhibitors can occur through secondary drug resistance mutations or alternate bypass mechanisms, highlighting the need for combinatorial drug strategies.