Emerging RET Inhibitors: Overcoming Resistance in RET-Altered Cancers

In May 2020, selpercatinib was the first-ever FDA-approved medication targeting the RET pathway, beneficial for treating non-small cell lung cancer (NSCLC) and thyroid cancer with RET fusions, as well as medullary thyroid cancer with RET mutations. However, patients may develop resistance to selpercatinib, often due to the emergence of RET G810 mutations that interfere with the drug's binding. Some patients also show resistance mutations at the RET V804 position, which is crucial for identifying new treatments that can overcome both types of resistance.

While there are multi-kinase inhibitors capable of targeting RET G810 mutations, they are ineffective against V804 mutations and can cause off-target side effects that reduce their effectiveness. A new series of potent and selective next-generation RET inhibitors has been identified to meet the needs of patients who relapse after treatment with selective RET inhibitors.

The potency of these inhibitors was tested in engineered HEK293 cell lines with various RET mutations, including M918T, KIF5B-RET fusion, and resistance mutations G810S and V804M. One molecule, LOX-18228, showed strong activity against all tested RET mutations with low nanomolar IC50 values. It also displayed high selectivity for RET over a panel of other kinases and was effective against a range of receptors, transporters, and enzymes at a 10 μM concentration. Additionally, LOX-18228 had a favorable hERG IC50 value and promising in vitro ADME properties, indicating good potential for in vivo exposure with low clearance rates across different species and high intestinal permeability.

In animal models, LOX-18228 showed high oral bioavailability and was effective in reducing tumor growth in patient-derived xenograft (PDX) models with RET G810S and V804M mutations, leading to complete regression or significant tumor growth inhibition at specific doses. These findings indicate that LOX-18228 and related compounds are promising candidates for next-generation RET inhibitors, which could potentially extend the duration of disease control for patients with RET-altered cancers who have developed resistance to existing treatments. Plans for an Investigational New Drug (IND) application are underway for 2021.