Mechanisms of resistance to selective RET tyrosine kinase inhibitors in RET fusion-positive non-small-cell lung cancer

Abstract

Background: Rearranged during transfection (RET) gene fusions are a validated target in non-small-cell lung cancer (NSCLC). RET-selective inhibitors selpercatinib (LOXO-292) and pralsetinib (BLU-667) recently demonstrated favorable antitumor activity and safety profiles in advanced RET fusion-positive NSCLC, and both have received approval by the US Food and Drug Administration for this indication. Insights into mechanisms of resistance to selective RET inhibitors remain limited. Patients and methods: This study was performed at five institutions. Tissue and/or cell-free DNA was obtained from patients with RET fusion-positive NSCLC after treatment with selpercatinib or pralsetinib and assessed by nextgeneration sequencing (NGS) or MET FISH. Results: We analyzed a total of 23 post-treatment tissue and/or plasma biopsies from 18 RET fusion-positive patients who received an RET-selective inhibitor (selpercatinib, n ¼ 10; pralsetinib, n ¼ 7; pralsetinib followed by selpercatinib, n ¼ 1, with biopsy after each inhibitor). Three cases had paired tissue and plasma samples, of which one also had two serial resistant tissue specimens. The median progression-free survival on RET inhibitors was 6.3 months [95% confidence interval 3.6e10.8 months]. Acquired RET mutations were identified in two cases (10%), both affecting the RET G810 residue in the kinase solvent front. Three resistant cases (15%) harbored acquired MET amplification without concurrent RET resistance mutations, and one specimen had acquired KRAS amplification. No other canonical driver alterations were identified by NGS. Among 16 resistant tumor specimens, none had evidence of squamous or small-cell histologic transformation. Conclusions: RET solvent front mutations are a recurrent mechanism of RET inhibitor resistance, although they occurred at a relatively low frequency. The majority of resistance to selective RET inhibition may be driven by RET-independent resistance such as acquired MET or KRAS amplification. Next-generation RET inhibitors with potency against RET resistance mutations and combination strategies are needed to effectively overcome resistance in these patients.

Kinase drug discovery 20 years after imatinib: progress and future directions

“…These RTKs then switch on the same downstream signalling pathways that would normally be activated by the mutant EGFR if it was not inhibited by the drug (that is, the RAF–MEK–ERK and PI3K–PDK1–AKT pathways) 109 . This phenomenon has also been observed in other NSCLC settings where the cells respond to inhibitors of mutant ALK by overexpressing the EGFR or KIT receptor, while MET amplification has been identified as an emerging resistance mechanism to RET inhibitors 110 . In breast cancer, resistance to agents targeting HER2 overexpression have similarly been associated with switching to alternative RTKs including MET, HER3 and IGF1R 111 , 112 .…”

Potential Unreliability of Uncommon ALK, ROS1, and RET Genomic Breakpoints in Predicting the Efficacy of Targeted Therapy in NSCLC

“…Many patients with ALK, ROS1, or RET fusion benefiting from matched targeted therapy will develop acquired resistance within 1 year, and a small fraction of patients were found to have progressive disease (PD) as their best response owing to intrinsic resistance. [5][6][7] High-throughput next-generation sequencing (NGS) is ideal for uncovering diverse genetic events in NSCLC. 8 Target-capture DNA NGS is capable of pinpointing breakpoints to specific base positions in the genome, and thus can identify variable fusion variants.…”

Diagnostics, therapeutics and RET inhibitor resistance for RET fusion–positive non-small cell lung cancers and future perspectives

“…For patients in which mutations in the RET kinase domain responsible for drug resistance were not detected, evidence exist mostly for the activation of bypass signaling pathways. MET dependence has been reported as a recurring and potentially targetable mechanism of resistance to selpercatinib and pralsetinib [81][82][83]. Preclinical studies have demonstrated that EGFR transduced bypass signals to critical downstream pathways which regulate cell proliferation and survival via ERK and AKT, enabling cancer cells to evade RET inhibitors.…”