Landscape of Genomic Mechanisms of Resistance to Selective RET Inhibitors in RET-Altered Solid Tumors: Analysis of the RETgistry Global Consortium
Recommended Citation
Waliany S, Cooper AJ, Liu SV, Gautschi O, Rotow JK, Smith KER, Weber UM, Lee DH, Loong HHF, Patel JD, Pennell NA, Nagasaka M, Patel SA, Tan DSW, Solomon BJ, Kim TM, Pall G, Riess JW, Sun L, Früh M, Uy NF, Gadgeel S, Feng J, Do A, Falcon C, Leighl NB, Baik CS, Lai GGY, Ou SI, Cheung KSY, Patil T, Mansfield AS, Weiler D, Yeap BY, Wirth LJ, Gainor JF, Drilon A, and Lin JJ. Landscape of Genomic Mechanisms of Resistance to Selective RET Inhibitors in RET-Altered Solid Tumors: Analysis of the RETgistry Global Consortium. Clin Cancer Res 2026;32(6):1157-1168.
Document Type
Article
Publication Date
3-16-2026
Publication Title
Clinical cancer research
Keywords
Humans, Proto-Oncogene Proteins c-ret, Drug Resistance, Neoplasm, Female, Male, Middle Aged, Protein Kinase Inhibitors, Aged, Mutation, Neoplasms, Adult, Genomics, Biomarkers, Tumor, High-Throughput Nucleotide Sequencing, Aged, 80 and over, Pyrazoles, Pyrimidines, Pyridines
Abstract
PURPOSE: Rearranged during transfection (RET) alterations are oncogenic drivers across solid tumors. Selective RET inhibitors (SRI) selpercatinib and pralsetinib have transformed outcomes for patients with RET-altered malignancies. Limited knowledge exists on genomic mechanisms of resistance to SRI.
EXPERIMENTAL DESIGN: We established "RETgistry," a global consortium of patients with advanced RET-altered solid tumors who received SRI and underwent postprogression tissue or plasma biopsies assessed by next-generation sequencing. Frequencies of secondary RET resistance mutations and acquired non-RET gene alterations were determined. Progression-free survival (PFS) and time to treatment discontinuation (TTD) on first SRI were estimated with the Kaplan-Meier method.
RESULTS: RETgistry included 109 patients with RET-altered advanced solid tumors (lung, n = 94; thyroid, n = 15) who underwent 143 post-SRI progression biopsies (tissue, 91; plasma, 52). The median PFS and TTD were 13.9 months [95% confidence interval (CI), 10.1-16.6] and 17.3 months (95% CI, 14-20.2), respectively. Secondary RET mutations were detected in 20 (14%) biopsies [lung cancer, 15 (12.4%) and thyroid carcinoma, 5 (22.7%)]. Common acquired off-target alterations involved MET (18.2%; amplification, 15%), TP53 (8.2%), APC (7.6%), KRAS (7.1%), KEAP1 (5.9%), and CDKN2A/B (5.3%). MET alterations were enriched in post-SRI versus pre-SRI specimens (full cohort, 17.6% vs. 2.0%, P = 0.022; lung cancer, 19.1% vs. 2.1%, P = 0.022).
CONCLUSIONS: The prevalence of secondary RET mutations after SRI was low, underscoring a greater role for off-target resistance. Recurrent acquired alterations involving tumor suppressor genes or upstream regulators of MAPK and PI3K pathways were identified, most commonly MET amplification. Continued efforts to characterize SRI resistance biology are critical to guide the development of novel therapeutic strategies.
Medical Subject Headings
Humans; Proto-Oncogene Proteins c-ret; Drug Resistance, Neoplasm; Female; Male; Middle Aged; Protein Kinase Inhibitors; Aged; Mutation; Neoplasms; Adult; Genomics; Biomarkers, Tumor; High-Throughput Nucleotide Sequencing; Aged, 80 and over; Pyrazoles; Pyrimidines; Pyridines
PubMed ID
41537704
ePublication
ePub ahead of print
Volume
32
Issue
6
First Page
1157
Last Page
1168
