Abstract 3278: Analysis of the mechanism of resistance to selpercatinib in thyroid cancer cells with RET/PTC1 fusion gene

Abstract

Abstract Purpose: Precision oncology, in which molecularly targeted drugs are selected based on genetic mutations, has begun in thyroid cancer, and drugs targeting BRAF, RET, and NTRK are already in clinical use. However, as with previous therapeutic agents for malignant tumors, there have been cases of resistance to these drugs either initially or during treatment, and the mechanisms of drug resistance need to be elucidated. So far, little is known about the mechanisms of resistance to molecularly targeted drugs in thyroid cancer. To overcome resistance to the RET inhibitor, selpercatinib (SEL), and to consider next therapeutic strategies, we aimed to elucidate the mechanisms of resistance to SEL. Method: We used papillary carcinoma cell lines TPC-1 and CUTC48, which harbor the RET/PTC1 fusion gene. We established an SEL-resistant subline (TPC-1/SELR) in TPC-1 by long-term exposure to SEL. The growth inhibitory effect of drugs was analyzed using the WST assay. The alteration of intracellular signal transduction was analyzed by western blotting. Result: The 50% inhibitory concentration (IC50) for SEL in the parental TPC-1 was 3 nM, while growth inhibition in TPC-1/SELR did not reach 50% even at more than 100 nM of SEL. On the other hand, growth inhibition by SEL in CUTC48 did not reach 50% even at more than 100 nM of SEL. The sensitivity to SEL in CUTC48 was comparable to that in TPC-1/SELR, and CUTC48 showed an intrinsic resistance to SEL. TPC-1/SELR showed increased phosphorylation of EGFR, Erk, Akt, and mTOR compared to TPC-1. In CUTC48, phosphorylation of EGFR and Erk was not increased compared to that of TPC-1, while phosphorylation of Akt and mTOR was increased. We investigated the growth inhibitory effect of an mTOR inhibitor everolimus and found that TPC-1 (IC50: 1.3 nM), TPC-1/SELR (5 nM), and CUTC48 (9.4 nM) were all highly sensitive to everolimus. Discussion: Our results showed that Akt and mTOR phosphorylation were elevated in the SEL-resistant TPC-1/SELR and the SEL-intrinsic resistant CUTC48 in common, suggesting the involvement of activation of the Akt-mTOR pathway in SEL resistance in thyroid cancer. The inhibition of the Akt-mTOR pathway in parallel with RET may have therapeutic potential to overcome SEL resistance in thyroid cancer. Citation Format: Masatsugu Amitani, Ken-ichi Ito. Analysis of the mechanism of resistance to selpercatinib in thyroid cancer cells with RET/PTC1 fusion gene [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3278.