Reference Detail

Ref Type

Journal Article

PMID

(37535881)

Authors

Porcelli T, Moccia M, De Stefano MA, Ambrosio R, Capoluongo E, Santoro M, Hadoux J, Schlumberger M, Carlomagno F, Salvatore D

Title

D898_E901 RET Deletion Is Oncogenic, Responds to Selpercatinib, and Treatment Resistance Can Arise Via RET-Independent Mechanisms.

Journal	Vol	Issue	Date	Pages	Journal Short Title
JCO precision oncology	7		2023 Aug	e2300052	JCO Precis Oncol

URL

Abstract Text

We analyzed the oncogenic potential of RET Δ898-901 mutant and its response to selpercatinib, vandetanib, and cabozantinib in vitro and in a clinical case.A 35-year-old man with a medullary thyroid cancer (MTC) harboring a somatic D898_E901 RET deletion was sequentially treated with vandetanib, selpercatinib, cabozantinib, and fluorouracil (5-FU)-dacarbazine. Functional study of RET Δ898-901 mutant was performed in HEK-293T, NIH-3T3, and Ba/F3 cells. RET C634R and wild-type cells served as positive and negative controls, respectively.The patient showed primary resistance to vandetanib and secondary resistance to selpercatinib after 12 months. Comprehensive next-generation sequencing of a progressing lesion during selpercatinib showed no additional RET mutation but an acquired complete genetic loss of CDKN2A, CDKN2B, and MTAP genes. Subsequent treatment with cabozantinib and 5-FU-dacarbazine had poor efficacy. In vitro, RET Δ898-901 showed higher ligand-independent RET autophosphorylation compared with RET C634R and similar proliferation rates in cell models. Subcutaneous injection of Δ898-901 NIH 3T3 cells in nude mice produced tumors of around 500 mm3 in 2 weeks, similarly to RET C634R cells. Selpercatinib inhibited cell growth of Ba/F3 RET Δ898-901 and RET C634R with a similar half maximal inhibitory concentration (IC50) of approximately 3 nM. Vandetanib was five-fold less effective at inhibiting cell growth promoted by RET Δ898-901 mutant (IC50, 564 nM) compared with RET C634R one (IC50, 91 nM). Cabozantinib efficiently inhibited Ba/F3 RET C634 proliferation (IC50, 25.9 nM), but was scarcely active in Ba/F3 RET 898-901 (IC50 > 1,350 nM).D898_E901 RET deletion is a gain-of-function mutation and responds to tyrosine kinase inhibitors in MTC. RET Δ898-901 mutant is sensitive to selpercatinib and vandetanib, and acquired resistance to selpercatinib may develop via RET-independent mechanisms.

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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
RET	D898_E901del	deletion	gain of function	RET D898_E901del results in the deletion of four amino acids in the protein kinase domain of the Ret protein from amino acids 898 to 901 (UniProt.org). D898_E901del confers a gain of function to Ret as demonstrated by increased Erk phosphorylation (PMID: 32284345), increased Ret phosphorlyation, (PMID: 37535881), cytokine-independent growth in culture (PMID: 32284345, PMID: 37535881), and tumor formation in a mouse model (PMID: 37535881).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
RET D898_E901del	Advanced Solid Tumor	predicted - sensitive	Vandetanib	Preclinical - Cell culture	Actionable	In a preclinical study, Caprelsa (vandetanib) inhibited Ret phosphorylation and proliferation in a transformed cell line expressing RET D898_E901del, but to a lesser degree than cells expressing RET C634R in culture (PMID: 37535881).	37535881
RET D898_E901del	Advanced Solid Tumor	sensitive	Selpercatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Retevmo (selpercatinib) inhibited Ret phosphorylation and proliferation in a transformed cell line expressing RET D898_E901del in culture (PMID: 37535881).	37535881
RET D898_E901del	thyroid gland medullary carcinoma	predicted - resistant	Vandetanib	Case Reports/Case Series	Actionable	In a clinical case study, a patient with metastatic medullary thyroid carcinoma harboring RET D898_E901del demonstrated primary resistance to Caprelsa (vandetanib) treatment (PMID: 37535881).	37535881
RET C634R	Advanced Solid Tumor	sensitive	Vandetanib	Preclinical - Cell culture	Actionable	In a preclinical study, Caprelsa (vandetanib) inhibited Ret phosphorylation and proliferation in a transformed cell line expressing RET C634R in culture (PMID: 37535881).	37535881
RET D898_E901del	thyroid gland medullary carcinoma	predicted - sensitive	Selpercatinib	Case Reports/Case Series	Actionable	In a clinical case study, Retevmo (selpercatinib) treatment resulted in a 61% reduction in the sum of the diameters of the target lesions in a patient with metastatic medullary thyroid carcinoma harboring RET D898_E901del, with treatment lasting 1 year (PMID: 37535881).	37535881
RET C634R	Advanced Solid Tumor	sensitive	Selpercatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Retevmo (selpercatinib) inhibited Ret phosphorylation and proliferation in a transformed cell line expressing RET C634R in culture (PMID: 37535881).	37535881
RET D898_E901del	Advanced Solid Tumor	resistant	Cabozantinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing RET D898_E901del were resistant to Cometriq (Cabometyx, cabozantinib) in culture (PMID: 37535881).	37535881