RET-driven cancer: the selective inhibitor landscape

RET spent two decades as a target that the field knew mattered but could only hit with dirty multikinase inhibitors. Cabozantinib and vandetanib worked partly through RET, but their off-target activity on VEGFR2 and other kinases capped the dose long before RET was fully shut down. The arrival of two purpose-built selective inhibitors in 2020 changed the picture entirely, and the resistance that followed is now teaching the field where the next chemistry has to go.

What RET actually is, and how it goes wrong

RET is a receptor tyrosine kinase. In cancer it is activated two different ways, and the distinction matters clinically because the same drugs treat both. In lung cancer, RET is almost always a fusion: a chromosomal rearrangement joins the RET kinase domain to a partner gene (KIF5B and CCDC6 are the common ones) whose promoter and dimerization domains drive constitutive, ligand-independent kinase activity. RET fusions occur in roughly 1 to 2 percent of non-small-cell lung cancer (NSCLC).

In medullary thyroid cancer (MTC) the lesion is usually a point mutation rather than a fusion. Germline RET mutations cause the inherited MEN2 syndromes, and somatic mutations at codon M918 (M918T) drive a large fraction of sporadic MTC. Papillary thyroid cancers carry RET fusions more like the lung pattern. The practical upshot: a single biomarker, RET activation, defines a tumor class that crosses tissue boundaries, which is exactly the setting where a tumor-agnostic approval makes sense.

The two selective inhibitors

Both compounds are ATP-competitive type I inhibitors designed for RET selectivity over the VEGFR2 activity that made the old multikinase drugs hard to tolerate. That selectivity is the whole point: it lets you push the dose to fully inhibit RET without the hypertension and other VEGFR2-driven toxicity that limited the predecessors.

• Selpercatinib (LOXO-292, Retevmo) — Loxo/Lilly. FDA accelerated approval May 2020 for RET fusion-positive NSCLC and RET-altered thyroid cancers, registered on the LIBRETTO-001 phase 1/2 basket trial. Response rates were high and durable across both treatment-naive and heavily pretreated patients. In September 2024 the agency converted the MTC indication to traditional approval and broadened a tumor-agnostic indication for RET fusion-positive solid tumors.
• Pralsetinib (BLU-667, Gavreto) — Blueprint/Roche. FDA approval September 2020 for RET fusion-positive NSCLC, on the ARROW phase 1/2 study, with thyroid indications following. Mechanistically close to selpercatinib; the two are generally considered interchangeable in efficacy, with differences mostly in toxicity handling and access.

Both penetrate the CNS reasonably well, which matters because RET fusion-positive NSCLC has a high rate of brain metastases, and intracranial responses were a notable feature of both trials.

The G810 wall

Selectivity bought efficacy but also funneled resistance into a narrow channel. Unlike KRAS G12C, where resistance is scattered across many bypass tracks, the dominant on-target escape from selective RET inhibition converges on a single residue: G810, the solvent-front position. Acquired G810C, G810S, and G810R mutations sit at the edge of the ATP pocket where the inhibitor projects toward solvent, and the larger side chains sterically clash with the drug.

What is striking is the convergent evolution. Post-progression biopsies and circulating-tumor-DNA studies have found different G810 substitutions arising in separate subclones within the same patient, all hitting the same residue independently. That is the cleanest possible evidence that the drug binds where the structural biology says it does, and that G810 is the load-bearing contact. The gatekeeper position (V804) was the feared resistance site by analogy to other kinases, but selpercatinib and pralsetinib were designed around it, so the pressure moved to the solvent front instead.

What comes after the solvent front

The next-generation RET inhibitors were built specifically to retain activity against G810. The road has been bumpy. TPX-0046 (enbezotinib) showed preclinical activity against G810 but its clinical program was terminated in 2023 over an unfavorable risk-benefit profile, and Lilly discontinued LOXO-260. Vepafestinib (TAS0953/HM06) has reported best-in-class RET selectivity with activity against L730, V804, and G810 variants and remains in clinical development. The lesson echoes the ALK and ROS1 stories: solvent-front resistance is chemically tractable, but building a next-generation inhibitor that covers it without picking up new toxicity is the hard part.

Try the docking yourself

The G810 solvent-front story is a textbook steric-clash resistance mechanism, and molecular docking shows it directly. Open Studio and pick RET from the target catalog with G810R or G810C from the mutation chips, then dock selpercatinib against both the wild-type and the mutant receptor side by side. The selective inhibitor that scores well against wild-type RET should lose ground against the solvent-front mutant as the bulkier residue intrudes on the binding pose. That delta, not the absolute score, is the resistance signal worth reading.

Liganx is molecular docking online: free, browser-based, and built for exactly this mutation-versus-wild-type comparison. If you want to try molecular docking on RET G810 resistance without a local install, that is the fastest path.

Primary sources

• Drilon A, et al. Efficacy of Selpercatinib in RET Fusion-Positive Non-Small-Cell Lung Cancer. NEJM 383, 813-824 (2020). doi:10.1056/NEJMoa2005653
• Gainor JF, et al. Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study. Lancet Oncol 22, 959-969 (2021). doi:10.1016/S1470-2045(21)00247-3
• Solomon BJ, et al. RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-Driven Malignancies. J Thorac Oncol 15, 541-549 (2020). doi:10.1016/j.jtho.2020.01.006
• U.S. FDA. FDA approves selpercatinib for locally advanced or metastatic RET fusion-positive solid tumors (2024). fda.gov