Reference Detail

Ref Type

abstract

PMID

Authors

Jaume Roca-Arias, Jordi Bertran-Alamillo, Ruth Román, Cristina Aguado, Laura López, Leticia Ferro-Leal, Beatriz Garcia-Pelaez, Rodrigo de Oliveira Cavagna, Silvia Teixeira, Rafael Rosell, Rui Manuel Reis, Miguel A. Molina-Vila, Ivana Sullivan

Title

Abstract 4039: RET overexpression is frequent in lung neuroendocrine tumors (NET) and associates with response to RET tyrosine kinase inhibitors (RET TKIs) in NET cell lines

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer Res	83	7_supplement	2023

URL

https://aacrjournals.org/cancerres/article/83/7_Supplement/4039/724679/Abstract-4039-RET-overexpression-is-frequent-in

Abstract Text

Background: RET (rearranged during transfection) is a proto-oncogene encoding for a tyrosine kinase membrane receptor that promotes protein synthesis and cell proliferation. A small percentage of human tumors harbor RET fusions or mutations as oncogenic drivers and RET-TKIs have been developed. Two of them, selpercatinib and pralsetinib, have recently been approved. However, their effect on tumors overexpressing wild-type RET (wt-RET) has not been investigated. A large-scale mRNA analysis performed by our group revealed that ~2% of lung tumors present high expression of wt-RET in absence of fusions. Interestingly, ~60% of high wt-RET tumors presented neuroendocrine characteristics. Methods: Twenty large cell neuroendocrine (LCNEC) and 19 small cell (SCLC) lung carcinomas from two additional institutions were analyzed by nCounter® to validate the previous results. For in vitro experiments, a panel of cell lines derived from lung NETs (DMS-53, NCI-H82, NCI-H727) was used, together with a lung adenocarcinoma cell line (LC2/ad, a positive control harboring the CDCC6-RET translocation). RET fusions and mRNA expression were analyzed by nCounter®, RET protein expression by Western blotting and immunohistochemistry (IHC) and RET mutations by next generation sequencing. The inhibitory effects of selpercatinib and pralsetinib were analyzed in vitro by MTT in 2D and spheroid/3D cultures. Finally, in vivo experiments implanting tumor cells into athymic nude mice are ongoing. Results: Among the 20 LCNECs and 19 SCLCs analyzed, 3 (15%) and 3 (15%) presented very high levels of wt-RET mRNA by nCounter, respectively. Fusions were absent in all cases. The NCI-H82 and NCI-H727 NET cell lines showed very low RET mRNA and protein expression by nCounter, Western blotting and IHC. In contrast, DMS-53 cells presented levels of RET mRNA and protein higher than the observed in the RET-fusion positive LC2/ad. In 2D models, the three NET cell lines tested showed moderate resistance to pralsetinib and selpercatinib, with IC50s of 1.5 - 9.7 µM for pralsetinib and 4.6 - 6.1 µM for selpercatinib; while the RET-fusion positive LC2/ad cells showed an IC50 in the nM range, as expected. In 3D cultures, DMS-53 was found to be sensitive to RET TKIs, with IC50s of and 0.3 µM for praseltinib and 2.5 µM for selpercatinib. In contrast, spheroids of the two RET low cell lines showed complete resistance to both drugs (IC50>10 µM). Experiments in animal models are currently ongoing, final results will be presented at the meeting. Conclusions: Overexpression of RET is frequent in lung tumors with neuroendocrine features (LCNEC, SCLC). Selpercatinib and Pralsetinib show antitumor activity in lung NETs cells expressing high levels of wt-RET.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
RET over exp	pulmonary neuroendocrine tumor	predicted - sensitive	Selpercatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Retevmo (selpercatinib) inhibited proliferation of a lung neuroendocrine tumor cell line with high RET expression in 3D spheroid culture (Cancer Res (2023) 83 (7_Supplement): 4039).	detail...
RET over exp	pulmonary neuroendocrine tumor	predicted - sensitive	Pralsetinib	Preclinical - Cell culture	Actionable	In a preclinical study, Gavreto (pralsetinib) inhibited proliferation of a lung neuroendocrine tumor cell line with high RET expression in 3D spheroid culture (Cancer Res (2023) 83 (7_Supplement): 4039).	detail...