Reference Detail

Ref Type

Journal Article

PMID

(32284345)

Authors

Zhao Z, Fu T, Gao J, Xu Y, Wu X, Chen W, Li X, Yu R, Shao YW, Li M, Yao Y

Title

Identifying novel oncogenic RET mutations and characterising their sensitivity to RET-specific inhibitors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of medical genetics			2020 Apr 13		J Med Genet

URL

Abstract Text

Rearranged during transfection (RET) is a well-known proto-oncogene. Multiple RET oncogenic alterations have been identified, including fusions and mutations. Although RET fusions have been reported in multiple cancers, RET mutations were mainly found in multiple endocrine neoplasia type 2 and medullary thyroid carcinoma. RET mutations in other cancers were underinvestigated and their functional annotation was less well studied.We retrospectively reviewed next-generation sequencing data from 37 056 patients with cancer to search for RET mutations. We excluded patients with other co-occurring known driver mutations to enrich potential activating RET mutations for further analysis. Moreover, we performed in vitro functional validation of the oncogenic property of several high frequent and novel RET mutants and their sensitivity to RET-specific inhibitors LOXO-292 and BLU-667.Within 560 (1.5%) patients with cancer who harbour RET mutations, we identified 380 distinct RET mutation sites, including 252 sites without co-occurring driver mutations. RET mutations were more frequently found in thyroid cancer, mediastinal tumour and several other cancers. The mutation sites spread out through the whole protein with a few hotspots within the kinase domain. In addition, we functionally validated that 898-901del, T930P and T930K were novel RET-activating mutations and they were all sensitive to RET inhibitors.Our results demonstrated the frequency of RET mutations across different cancers. We reported and/or validated several previously uncharacterised RET oncogenic mutations and demonstrated their sensitivity to RET-specific inhibitors. Our results help to stratify patients with cancer based on their RET mutation status and potentially provide more targeted treatment options.

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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
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).
RET	E136K	missense	unknown	RET E136K lies within the extracellular domain of the Ret protein (UniProt.org). E136K has been identified in sequencing studies (PMID: 32284345), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Feb 2024).
RET	K662M	missense	unknown	RET K662M lies within the cytoplasmic domain of the Ret protein (UniProt.org). K662M has been identified in sequencing studies (PMID: 34741450, PMID: 32284345), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jan 2024).
RET	M1008I	missense	unknown	RET M1008I lies within the protein kinase domain of the Ret protein (UniProt.org). M1008I has been identified in sequencing studies (PMID: 32284345), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2024).
RET	R133C	missense	unknown	RET R133C lies within the extracellular domain of the Ret protein (UniProt.org). R133C has been identified in sequencing studies (PMID: 32284345, PMID: 34741450), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jan 2024).
RET	R177W	missense	unknown	RET R177W lies within the cadherin domain of the Ret protein (UniProt.org). R177W has been identified in sequencing studies (PMID: 34741450, PMID: 32284345), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jan 2024).
RET	R721W	missense	unknown	RET R721W lies within the cytoplasmic domain of the Ret protein (UniProt.org). R721W has been identified in sequencing studies (PMID: 32284345), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Feb 2024).
RET	R77L	missense	unknown	RET R77L lies within the extracellular domain of the Ret protein (UniProt.org). R77L has been identified in the scientific literature (PMID: 25530832, PMID: 29681454, PMID: 32284345), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Feb 2024).
RET	T742M	missense	unknown	RET T742M lies within the protein kinase domain of the Ret protein (UniProt.org). T742M has been identified in the scientific literature (PMID: 31712133, PMID: 32284345), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Feb 2024).
RET	T930K	missense	gain of function - predicted	RET T930K lies within the protein kinase domain of the Ret protein (UniProt.org). T930K results in Erk phosphorylation similar to wild-type Ret but cytokine-independent growth in culture (PMID: 32284345), and therefore, is predicted to lead to a gain of Ret protein function.
RET	T930M	missense	no effect - predicted	RET T930M lies within the protein kinase domain of the Ret protein (UniProt.org). T930M results in Erk phosphorylation similar to wild-type Ret and does not result in cytokine-independent growth in culture (PMID: 32284345), and therefore, is predicted to have no effect on Ret protein function.
RET	T930P	missense	gain of function - predicted	RET T930P lies within the protein kinase domain of the Ret protein (UniProt.org). T930P results in Erk phosphorylation similar to wild-type Ret but cytokine-independent growth in culture (PMID: 32284345), and therefore, is predicted to lead to a gain of Ret protein function.

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
RET T930K	Advanced Solid Tumor	sensitive	Pralsetinib	Preclinical - Cell culture	Actionable	In a preclinical study, Gavreto (pralsetinib) inhibited growth of transformed cells expressing RET T930K in culture (PMID: 32284345).	32284345
RET T930P	Advanced Solid Tumor	sensitive	Selpercatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Retevmo (selpercatinib) inhibited growth of transformed cells expressing RET T930P in culture (PMID: 32284345).	32284345
RET M918T	Advanced Solid Tumor	sensitive	Pralsetinib	Preclinical - Cell culture	Actionable	In a preclinical study, Gavreto (pralsetinib) inhibited Erk phosphorylation and growth of transformed cells expressing RET M918T in culture (PMID: 32284345).	32284345
RET T930P	Advanced Solid Tumor	sensitive	Pralsetinib	Preclinical - Cell culture	Actionable	In a preclinical study, Gavreto (pralsetinib) inhibited growth of transformed cells expressing RET T930P in culture (PMID: 32284345).	32284345
RET D898_E901del	Advanced Solid Tumor	sensitive	Pralsetinib	Preclinical - Cell culture	Actionable	In a preclinical study, Gavreto (pralsetinib) inhibited Erk phosphorylation and growth of transformed cells expressing RET D898_E901del in culture (PMID: 32284345).	32284345
RET D898_E901del	Advanced Solid Tumor	sensitive	Selpercatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Retevmo (selpercatinib) inhibited Erk phosphorylation and growth of transformed cells expressing RET D898_E901del in culture (PMID: 32284345).	32284345
RET T930K	Advanced Solid Tumor	sensitive	Selpercatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Retevmo (selpercatinib) inhibited growth of transformed cells expressing RET T930K in culture (PMID: 32284345).	32284345
RET M918T	Advanced Solid Tumor	sensitive	Selpercatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Retevmo (selpercatinib) inhibited Erk phosphorylation and growth of transformed cells expressing RET M918T in culture (PMID: 32284345).	32284345