Establishment of RET inhibitor-induced resistant patient-derived colorectal cancer xenograft models

Background: Rearranged during transfection (RET), a transmembrane receptor tyrosine kinase, is involved in multi-system tissue development which includes nervous, hematopoietic, and gastrointestinal systems. Activating RET alteration, induced by gene fusions or point mutations, has been discovered several different solid tumor types including thyroid cancer, non-small cell lung cancer (NSCLC), breast colorectal cancer. Recently, two RET-specific kinase inhibitors (TKIs), selpercatinib (LOXO-292) pralsetinib (BLU-667), were approved the FDA for treatment of NSCLC. Despite encouraging efficacy these inhibitors, acquired resistance, such as solvent-front G810R/S/C mutations limited their clinical benefits. Therefore, to better investigate novel therapeutic strategies can overcome we established patient-derived xenograft (PDX) models with drug-induced resistance. Methods: CR2518, PDX model CCDC6-RET fusion gene, was implanted subcutaneously treated LOXO-292 at 3 mg/kg, twice daily, 116 days. Recurrent tumors isolated, cryopreserved mutation analyzed RNA sequencing (RNA-seq) verified PCR. The harboring transplanted into mice, bearing mice mean volumes 150–200 mm3 mg/kg 10 mg/ kg, 21 changes volume over time used evaluate anti-tumor vivo. Results: vigorously inhibited growth complete regression seen all ten on day 63 after CR2518. However, re-growth observed nine out from onwards. RNA-seq data demonstrated that gatekeeper V804M found 7 9 tumors, 4 them co-occurred an solvent front G810S mutation. Additionally, homozygous other tumors. Furthermore, could be still suppressed upon kg mice. Whereas, became resistant even when dosing level increased Conclusion: successfully inhibitor-induced become useful tool next generation inhibitors. No conflict interest.