Reference Detail

Ref Type

Journal Article

PMID

(25295501)

Authors

Wagle N, Grabiner BC, Van Allen EM, Amin-Mansour A, Taylor-Weiner A, Rosenberg M, Gray N, Barletta JA, Guo Y, Swanson SJ, Ruan DT, Hanna GJ, Haddad RI, Getz G, Kwiatkowski DJ, Carter SL, Sabatini DM, Janne PA, Garraway LA, Lorch JH

Title

Response and acquired resistance to everolimus in anaplastic thyroid cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
The New England journal of medicine	371	15	2014 Oct 9	1426-33	N Engl J Med

URL

Abstract Text

Everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is effective in treating tumors harboring alterations in the mTOR pathway. Mechanisms of resistance to everolimus remain undefined. Resistance developed in a patient with metastatic anaplastic thyroid carcinoma after an extraordinary 18-month response. Whole-exome sequencing of pretreatment and drug-resistant tumors revealed a nonsense mutation in TSC2, a negative regulator of mTOR, suggesting a mechanism for exquisite sensitivity to everolimus. The resistant tumor also harbored a mutation in MTOR that confers resistance to allosteric mTOR inhibition. The mutation remains sensitive to mTOR kinase inhibitors.

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Molecular Profile	Treatment Approach
TSC2 F615S	mTORC1 Inhibitor
TSC2 N1064Kfs*104	mTORC1 Inhibitor
TSC2 L1597Rfs*4	mTOR Inhibitor
TSC2 P28fs	mTORC1 Inhibitor
TSC2 Q200fs	mTOR Inhibitor
TSC2 N275del	mTORC1 Inhibitor
TSC2 G305*	mTORC1 Inhibitor
TSC2 V1547I	mTOR Inhibitor
TSC2 V299fs	mTORC1 Inhibitor
TSC2 T1068I	mTORC1 Inhibitor
TSC2 Q1503*	mTOR Inhibitor
TSC2 Q1178*	mTOR Inhibitor
TSC2 L1750Afs*25	mTORC1 Inhibitor
TSC2 R901C	mTORC1 Inhibitor
TSC2 G654Efs*45	mTORC1 Inhibitor
TSC2 L916P	mTORC1 Inhibitor
TSC2 T147K	mTOR Inhibitor
TSC2 M280T	mTOR Inhibitor
TSC2 W1208*	mTORC1 Inhibitor
TSC2 V1646G	mTORC1 Inhibitor
TSC2 H1746_R1751del	mTOR Inhibitor
TSC2 R622W	mTOR Inhibitor
TSC2 E96*	mTORC1 Inhibitor
TSC2 C696Y	mTOR Inhibitor
TSC2 R751*	mTORC1 Inhibitor
TSC2 R1138*	mTOR Inhibitor
TSC2 P28fs	mTOR Inhibitor
TSC2 I1561Hfs*5	mTORC1 Inhibitor
TSC2 W304Ffs*27	mTOR Inhibitor
TSC2 W1208*	mTOR Inhibitor
TSC2 R308W	mTOR Inhibitor
TSC2 V909Cfs*6	mTOR Inhibitor
TSC2 C900*	mTOR Inhibitor
TSC2 R1743W	mTOR Inhibitor
TSC2 K347Efs*36	mTOR Inhibitor
TSC2 E138*	mTORC1 Inhibitor
TSC2 S1723*	mTORC1 Inhibitor
TSC2 G1544V	mTORC1 Inhibitor
TSC2 N1643H	mTORC1 Inhibitor
TSC2 L1750Afs*25	mTOR Inhibitor
TSC2 S1798A	mTOR Inhibitor
TSC2 Q112*	mTOR Inhibitor
TSC2 H1617Y	mTORC1 Inhibitor
TSC2 V1547I	mTORC1 Inhibitor
TSC2 K347Efs*36	mTORC1 Inhibitor
TSC2 F1668L	mTORC1 Inhibitor
TSC2 T147K	mTORC1 Inhibitor
TSC2 S1723*	mTOR Inhibitor
TSC2 R1459*	mTORC1 Inhibitor
TSC2 Q112*	mTORC1 Inhibitor
TSC2 D1512A	mTOR Inhibitor
TSC2 D1690fs	mTORC1 Inhibitor
TSC2 R611W	mTOR Inhibitor
TSC2 R905fs	mTORC1 Inhibitor
TSC2 A1003fs	mTOR Inhibitor
TSC2 R622W	mTORC1 Inhibitor
TSC2 C900*	mTORC1 Inhibitor
TSC2 S1085fs	mTOR Inhibitor
TSC2 N1064Kfs*104	mTOR Inhibitor
TSC2 S1045F	mTOR Inhibitor
TSC2 H1718P	mTOR Inhibitor
TSC2 A607E	mTOR Inhibitor
TSC2 E114*	mTORC1 Inhibitor
TSC2 V504D	mTOR Inhibitor
TSC2 G294E	mTOR Inhibitor
TSC2 loss	mTOR Inhibitor
TSC2 R611Q	mTORC1 Inhibitor
TSC2 V769E	mTORC1 Inhibitor
TSC2 D1512A	mTORC1 Inhibitor
TSC2 G305*	mTOR Inhibitor
TSC2 D1598fs	mTORC1 Inhibitor
TSC2 loss	mTORC1 Inhibitor
TSC2 R901C	mTOR Inhibitor
TSC2 V1067E	mTORC1 Inhibitor
TSC2 Q1192*	mTORC1 Inhibitor
TSC2 V1199G	mTOR Inhibitor
TSC2 E114*	mTOR Inhibitor
TSC2 R98W	mTORC1 Inhibitor
TSC2 L264Wfs*73	mTOR Inhibitor
TSC2 A1349Gfs*64	mTORC1 Inhibitor
TSC2 F615S	mTOR Inhibitor
TSC2 G294E	mTORC1 Inhibitor
TSC2 V1623G	mTORC1 Inhibitor
TSC2 S1045F	mTORC1 Inhibitor
TSC2 V1199G	mTORC1 Inhibitor
TSC2 Q785*	mTOR Inhibitor
TSC2 I365del	mTOR Inhibitor
TSC2 Q325*	mTORC1 Inhibitor
TSC2 R905Q	mTOR Inhibitor
TSC2 T1068I	mTOR Inhibitor
TSC2 P1176fs	mTOR Inhibitor
TSC2 Q785*	mTORC1 Inhibitor
TSC2 R611W	mTORC1 Inhibitor
TSC2 V909Cfs*6	mTORC1 Inhibitor
TSC2 L369P	mTOR Inhibitor
TSC2 T1059Nfs*109	mTORC1 Inhibitor
TSC2 R1200P	mTORC1 Inhibitor
TSC2 R505*	mTOR Inhibitor
TSC2 R1743W	mTORC1 Inhibitor
TSC2 D1690fs	mTOR Inhibitor
TSC2 R905fs	mTOR Inhibitor
TSC2 C696Y	mTORC1 Inhibitor
TSC2 L264Wfs*73	mTORC1 Inhibitor
TSC2 I365del	mTORC1 Inhibitor
TSC2 I1197F	mTOR Inhibitor
TSC2 Q90*	mTORC1 Inhibitor
TSC2 V1623G	mTOR Inhibitor
TSC2 N275del	mTOR Inhibitor
TSC2 W304Ffs*27	mTORC1 Inhibitor
TSC2 M280T	mTORC1 Inhibitor
TSC2 F1668L	mTOR Inhibitor
TSC2 R611Q	mTOR Inhibitor
TSC2 E652fs	mTOR Inhibitor
TSC2 R1200P	mTOR Inhibitor
TSC2 H1718P	mTORC1 Inhibitor
TSC2 V299fs	mTOR Inhibitor
TSC2 E96*	mTOR Inhibitor
TSC2 R1720Q	mTORC1 Inhibitor
TSC2 L369P	mTORC1 Inhibitor
TSC2 R905Q	mTORC1 Inhibitor
TSC2 del	mTOR Inhibitor
TSC2 S1085fs	mTORC1 Inhibitor
TSC2 V1067E	mTOR Inhibitor
TSC2 R1459*	mTOR Inhibitor
TSC2 P1176fs	mTORC1 Inhibitor
TSC2 Q417*	mTOR Inhibitor
TSC2 A1349Gfs*64	mTOR Inhibitor
TSC2 R1138*	mTORC1 Inhibitor
TSC2 R98W	mTOR Inhibitor
TSC2 R458*	mTORC1 Inhibitor
TSC2 E138*	mTOR Inhibitor
TSC2 G654Efs*45	mTOR Inhibitor
TSC2 Q325*	mTOR Inhibitor
TSC2 del	mTORC1 Inhibitor
TSC2 inact mut	mTOR Inhibitor
TSC2 D514Pfs*74	mTOR Inhibitor
TSC2 D1598fs	mTOR Inhibitor
TSC2 G1544V	mTOR Inhibitor
TSC2 A614D	mTOR Inhibitor
TSC2 Q1192*	mTOR Inhibitor
TSC2 Q90*	mTOR Inhibitor
TSC2 A614D	mTORC1 Inhibitor
TSC2 L916P	mTOR Inhibitor
TSC2 V769E	mTOR Inhibitor
TSC2 Q1178*	mTORC1 Inhibitor
TSC2 V1646G	mTOR Inhibitor
TSC2 Q1503*	mTORC1 Inhibitor
TSC2 L1597Rfs*4	mTORC1 Inhibitor
TSC2 E652fs	mTORC1 Inhibitor
TSC2 Q417*	mTORC1 Inhibitor
TSC2 H1746_R1751del	mTORC1 Inhibitor
TSC2 I1197F	mTORC1 Inhibitor
TSC2 T1059Nfs*109	mTOR Inhibitor
TSC2 S1798A	mTORC1 Inhibitor
TSC2 R458*	mTOR Inhibitor
TSC2 A1003fs	mTORC1 Inhibitor
TSC2 I1561Hfs*5	mTOR Inhibitor
TSC2 V504D	mTORC1 Inhibitor
TSC2 H1617Y	mTOR Inhibitor
TSC2 N1643H	mTOR Inhibitor
TSC2 R505*	mTORC1 Inhibitor
TSC2 A607E	mTORC1 Inhibitor
TSC2 R308W	mTORC1 Inhibitor
TSC2 R751*	mTOR Inhibitor
TSC2 R1720Q	mTOR Inhibitor
TSC2 D514Pfs*74	mTORC1 Inhibitor
TSC2 inact mut	mTORC1 Inhibitor
TSC2 Q200fs	mTORC1 Inhibitor

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
TSC2 Q1178*	thyroid cancer	predicted - sensitive	Everolimus	Case Reports/Case Series	Actionable	In a clinical case study, a thyroid cancer patient harboring TSC2 Q1178* demonstrated an 18-month response to Afinitor (everolimus) (PMID: 25295501; NCT00936858).	25295501