RET K666E: Gene Variant Detail - Cancer Knowledgebase (CKB)

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Gene	RET
Variant	K666E
Impact List	missense
Protein Effect	gain of function
Gene Variant Descriptions	RET K666E lies within the cytoplasmic domain of the Ret protein (UniProt.org). K666E results in increased Erk1/2 phosphorylation and is transforming in culture (PMID: 21690267).
Associated Drug Resistance
Category Variants Paths	RET mutant RET act mut RET K666E

Variant Reference Transcript
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Transcript	NM_020975.6
gDNA	chr10:g.43114596A>G
cDNA	c.1996A>G
Protein	p.K666E
Source Database	RefSeq
Genome Build	GRCh38/hg38

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Showing 1 to 14 of 14 entries

Transcript	gDNA	cDNA	Protein	Source Database	Genome Build
NM_001406743.1	chr10:g.43114596A>G	c.1996A>G	p.K666E	RefSeq	GRCh38/hg38
NM_001406744.1	chr10:g.43114596A>G	c.1996A>G	p.K666E	RefSeq	GRCh38/hg38
NM_001406759.1	chr10:g.43114596A>G	c.1996A>G	p.K666E	RefSeq	GRCh38/hg38
NM_001406760.1	chr10:g.43114596A>G	c.1996A>G	p.K666E	RefSeq	GRCh38/hg38
NM_001406779.1	chr10:g.43123762A>G	c.1996A>G	p.K666E	RefSeq	GRCh38/hg38
NM_001406780.1	chr10:g.43123762A>G	c.1996A>G	p.K666E	RefSeq	GRCh38/hg38
NM_001406781.1	chr10:g.43123762A>G	c.1996A>G	p.K666E	RefSeq	GRCh38/hg38
NM_001406782.1	chr10:g.43123762A>G	c.1996A>G	p.K666E	RefSeq	GRCh38/hg38
NM_020630	chr10:g.43114596A>G	c.1996A>G	p.K666E	RefSeq	GRCh38/hg38
NM_020630.5	chr10:g.43114596A>G	c.1996A>G	p.K666E	RefSeq	GRCh38/hg38
NM_020630.7	chr10:g.43114596A>G	c.1996A>G	p.K666E	RefSeq	GRCh38/hg38
NM_020975	chr10:g.43114596A>G	c.1996A>G	p.K666E	RefSeq	GRCh38/hg38
NM_020975.5	chr10:g.43114596A>G	c.1996A>G	p.K666E	RefSeq	GRCh38/hg38
NM_020975.6	chr10:g.43114596A>G	c.1996A>G	p.K666E	RefSeq	GRCh38/hg38

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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
RET mutant	medullary thyroid carcinoma	sensitive	Selpercatinib	FDA approved - Has Companion Diagnostic	Actionable	In a Phase I/II trial (LIBRETTO-121) that supported FDA approval, Retevmo (selpercatinib) treatment was safe in pediatric patients of 2 years or older with solid tumors (8 medullary thyroid cancer, 2 papillary thyroid cancer, 1 osteosarcoma) harboring RET fusion (n=2) or mutations (n=9), and resulted in unconfirmed partial responses in 4 patients, stable disease in 6 patients (two lasting >/=16 weeks) (JCO 39, 10009-10009(2021); NCT03899792).	detail... detail... detail...
RET mutant	medullary thyroid carcinoma	sensitive	Selpercatinib	FDA approved - Has Companion Diagnostic	Actionable	In a Phase I/II trial (LIBRETTO-001) that supported FDA approval, Retevmo (selpercatinib) treatment resulted in an objective response rate (ORR) of 69% (38/55), with five complete and 33 partial responses, in adult and pediatric patients of 12 years and older with medullary thyroid cancer harboring RET mutations who were previously treated, while patients who had not been previously treated demonstrated an ORR of 73% (64/88), with ten complete and 54 partial responses (PMID: 32846061; NCT03157128).	detail... detail... 32846061
RET mutant	medullary thyroid carcinoma	sensitive	Selpercatinib	Guideline	Actionable	Retevmo (selpercatinib) is included in guidelines for patients with medullary thyroid carcinoma harboring RET mutations (NCCN.org).	detail...
RET mutant	medullary thyroid carcinoma	sensitive	Selpercatinib	Guideline	Actionable	Retevmo (selpercatinib) is included in guidelines for adult or pediatric patients 12 years or older with advanced medullary thyroid gland carcinoma harboring RET mutations (PMID: 31549998, PMID: 35491008; ESMO.org).	31549998 detail... 35491008
RET mutant	medullary thyroid carcinoma	sensitive	Pralsetinib	Guideline	Actionable	Gavreto (pralsetinib) is included in guidelines for adult or pediatric patients 12 years or older with advanced or metastatic medullary thyroid gland carcinoma harboring RET mutations (PMID: 31549998, PMID: 35491008; ESMO.org).	31549998 detail... 35491008
RET mutant	medullary thyroid carcinoma	sensitive	Pralsetinib	Guideline	Actionable	Gavreto (pralsetinib) is included in guidelines (category 2B) for patients with medullary thyroid carcinoma harboring RET mutations (NCCN.org).	detail...
RET mutant	medullary thyroid carcinoma	sensitive	Cabozantinib	Phase III	Actionable	In a Phase III trial, Cometriq (cabozantinib) treatment resulted in improved progression free survival (60 vs 20 weeks) compared to placebo in thyroid medullary carcinoma patients harboring RET mutations (PMID: 27525386).	27525386
RET mutant	medullary thyroid carcinoma	sensitive	Everolimus	Phase II	Actionable	In a Phase II trial, Afinitor (everolimus) treatment resulted in stable disease in 71% (5/7) of medullary thyroid cancer patients, including patients harboring RET mutations, with median progression-free survival of 33 weeks (PMID: 26294908; NCT01118065).	26294908
RET mutant	medullary thyroid carcinoma	sensitive	Pralsetinib	Phase Ib/II	Actionable	In a Phase I/II trial (ARROW), Gavreto (pralsetinib) treatment was well-tolerated and resulted in an overall response rate (ORR) of 60% (3/55) in patients with advanced or metastatic medullary thyroid cancer harboring RET mutations who received prior treatments, ORR was 60% (32/53) in patients with prior therapies and 71% (15/21) in treatment-naive patients (PMID: 34118198; NCT03037385).	34118198
RET mutant	lung non-small cell carcinoma	predicted - sensitive	EP0031	Phase Ib/II	Actionable	In a Phase I/II trial (KL400-I/II-01), EP0031 treatment was well tolerated in non-small cell lung cancer (NSCLC) patients harboring RET mutations, and resulted in an objective response rate (ORR) of 63% (20/32, 1 complete response (CR)) and disease control rate (DCR) of 91% in pretreated patients, and an ORR of 76% (19/25, 1 CR) and DCR of 92% with median duration of response not reached in treatment-naive patients, and an overall CNS DCR of 100% (J Clin Oncol 41, 2023 (suppl 16; abstr 3007); NCT05265091).	detail...
RET mutant	Advanced Solid Tumor	predicted - sensitive	EP0031	Phase Ib/II	Actionable	In a Phase I/II trial (KL400-I/II-01), EP0031 treatment was well tolerated and demonstrated preliminary activity in patients with advanced solid tumors harboring mutations in RET, resulting in an objective response rate of 64%, with responses being observed in patients with non-small cell lung cancer, medullary thyroid cancer and pancreatic cancer (J Clin Oncol 41, 2023 (suppl 16; abstr 3007); NCT05265091).	detail...
RET mutant	lung non-small cell carcinoma	unknown	unspecified immune checkpoint inhibitor	Clinical Study - Cohort	Actionable	In a retrospective clinical study, patients with non-small cell lung cancer harboring rare targetable drivers (RTD) (BRAF, ERBB2/3, RET, MET, ROS1, NTRK) who received immune checkpoint inhibitors (ICI) achieved longer median overall survival (mOS) (32 vs 13 mo, p=0.01) compared to those who did not receive ICI, mOS was 44.9 mo in a patient harboring RET mutation, although RTD type was not associated with OS in a univariate analysis (PMID: 30268448).	30268448
RET mutant	pheochromocytoma	predicted - sensitive	Sunitinib	Case Reports/Case Series	Actionable	In a Phase II trial (SNIPP), a patient with pheochromocytoma harboring a germline RET mutation achieved a partial response to treatment with Sutent (sunitinib), and demonstrated a 64% reduction in tumor volume and remained on treatment for over 7 years (PMID: 31105270).	31105270
RET mutant	Advanced Solid Tumor	sensitive	Ponatinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Iclusig (ponatinib) inhibited proliferation of cancer cell lines harboring RET mutations in cultured and in cell line xenograft models (PMID: 23526464).	23526464
RET act mut	lung non-small cell carcinoma	sensitive	Ponatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Iclusig (ponatinib) inhibited RET phosphorylation and reduced viability of non-small cell lung cancer cells with RET activating mutations (Cancer Res April 15, 2013 73; 2084).	detail...
RET mutant	cancer	sensitive	Sorafenib	Preclinical	Actionable	In a preclinical study, Nexavar (sorafenib) inhibited wild-type RET and RET mutations to prevent cell proliferation in cell culture (PMID: 17664273).	17664273
RET mutant	colorectal cancer	sensitive	Ponatinib	Preclinical	Actionable	In a preclinical study, Iclusig (ponatinib) demonstrated efficacy in RET mutant positive colorectal cancer cell lines (PMID: 23811235).	23811235

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RET K666E - Gene Variant Detail

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