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Ref Type Journal Article
PMID (21831957)
Authors Jin N, Jiang T, Rosen DM, Nelkin BD, Ball DW
Title Synergistic action of a RAF inhibitor and a dual PI3K/mTOR inhibitor in thyroid cancer.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 17
Issue 20
Date 2011 Oct 15
URL
Abstract Text In thyroid cancer clinical trials, agents targeting VEGF receptors (VEGFR) and RET, among other kinases, have led to partial responses but few complete or durable responses. The RAF-MEK-ERK and PI3K-AKT-mTOR signaling pathways are frequently activated in differentiated and medullary thyroid cancer (DTC and MTC) and may provide therapeutic targets for these diseases. We tested a novel drug combination targeting RAF, phosphoinositide 3-kinase (PI3K), and mTOR, plus VEGFR2 and RET, in thyroid cancer preclinical models with defined genetic backgrounds.RAF265, an ATP-competitive pan-RAF inhibitor active against VEGFR2, and BEZ-235, a PI3K inhibitor also active against Torc1 and Torc2, were tested alone and in combination in a panel of thyroid cancer lines. We tested RAF265 and BEZ-235 for kinase inhibition, growth inhibition and cell-cycle alterations, and inhibition of signaling targets and tumor growth in xenograft models.Both drugs potently inhibited their kinase targets in the extracellular signal-regulated kinase (ERK) and PI3K pathways. In addition, RAF265 had significant RET inhibitory activity (IC₅₀ = 25-50 nmol/L for RET(C634W)). The combination strongly inhibited proliferation of DTC and MTC cell lines with mutations in RAS, BRAF, PTEN, and RET. Synergy was shown for B-CPAP (BRAF(V600E)) and TT cells (RET(C634W)). The combination of both drugs significantly inhibited growth of CAL62 (KRAS(G12R/G12R)) and TT xenografts, thoroughly inhibiting ERK and PI3K pathway signaling.Combined blockade of ERK and PI3K signaling potently inhibits growth in preclinical models representing the key genotypes seen in refractory thyroid cancer. These targets and therapies are promising for further development in both differentiated and medullary thyroid cancers.

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Molecular Profile Treatment Approach
HRAS K117N PIK3CD inhibitor
HRAS Q61I PIK3CA inhibitor
HRAS A146T PIK3CA inhibitor
HRAS G12R PI3K Inhibitor (Pan)
HRAS A59T PIK3CD inhibitor
HRAS K117R PI3K Inhibitor (Pan)
HRAS G12Q PIK3CD inhibitor
HRAS A59T PIK3CA inhibitor
HRAS Q61F PIK3CD inhibitor
HRAS Q61H PIK3CA inhibitor
HRAS A59T PIK3CG inhibitor
HRAS G12X PI3K Inhibitor (Pan)
HRAS T58I PIK3CB inhibitor
HRAS T58I PIK3CD inhibitor
HRAS K117E PIK3CB inhibitor
HRAS Q61A PI3K Inhibitor (Pan)
HRAS Q61G PIK3CB inhibitor
HRAS G13I PIK3CA inhibitor
HRAS G13D PIK3CB inhibitor
HRAS G13D PI3K Inhibitor (Pan)
HRAS G12W PIK3CG inhibitor
HRAS Q61N PI3K Inhibitor (Pan)
HRAS G12Q PIK3CA inhibitor
HRAS Q61W PIK3CG inhibitor
HRAS G12C PIK3CA inhibitor
HRAS G12S PIK3CG inhibitor
HRAS Q61X PIK3CB inhibitor
HRAS G12M PI3K Inhibitor (Pan)
HRAS A59T PIK3CB inhibitor
HRAS Q61K PI3K Inhibitor (Pan)
HRAS Q61C PIK3CA inhibitor
HRAS K117R PIK3CG inhibitor
HRAS G13V PIK3CG inhibitor
HRAS Q61G PI3K Inhibitor (Pan)
HRAS Q61I PI3K Inhibitor (Pan)
HRAS G13T PIK3CD inhibitor
HRAS Q61V PI3K Inhibitor (Pan)
HRAS G12R PIK3CD inhibitor
HRAS G12H PIK3CG inhibitor
HRAS G13X PIK3CA inhibitor
HRAS G12R PIK3CA inhibitor
HRAS Q61M PIK3CD inhibitor
HRAS Q61K PIK3CA inhibitor
HRAS Q61L PIK3CD inhibitor
HRAS G12T PIK3CA inhibitor
HRAS G12W PIK3CA inhibitor
HRAS K117R PIK3CB inhibitor
HRAS K117N PIK3CG inhibitor
HRAS Q61M PIK3CG inhibitor
HRAS Q61K PIK3CB inhibitor
HRAS G12R PIK3CG inhibitor
HRAS G12S PIK3CD inhibitor
HRAS Q61F PIK3CA inhibitor
HRAS K117N PIK3CB inhibitor
HRAS G12M PIK3CB inhibitor
HRAS Q61L PI3K Inhibitor (Pan)
HRAS G12C PIK3CB inhibitor
HRAS G12A PIK3CB inhibitor
HRAS K117R PIK3CD inhibitor
HRAS Q61E PIK3CD inhibitor
HRAS G13C PIK3CG inhibitor
HRAS G12H PI3K Inhibitor (Pan)
HRAS Q61T PIK3CA inhibitor
HRAS Q61G PIK3CA inhibitor
HRAS G13I PIK3CG inhibitor
HRAS G12V PI3K Inhibitor (Pan)
HRAS G12A PIK3CA inhibitor
HRAS G12M PIK3CA inhibitor
HRAS G12Y PIK3CB inhibitor
HRAS G12D PIK3CB inhibitor
HRAS G12T PI3K Inhibitor (Pan)
HRAS Q61W PI3K Inhibitor (Pan)
HRAS Q61M PIK3CA inhibitor
HRAS G12V PIK3CB inhibitor
HRAS Q61R PIK3CG inhibitor
HRAS A146V PIK3CB inhibitor
HRAS G13C PIK3CA inhibitor
HRAS Q61P PIK3CD inhibitor
HRAS G13I PIK3CB inhibitor
HRAS G13C PIK3CD inhibitor
HRAS G12D PI3K Inhibitor (Pan)
HRAS T58I PI3K Inhibitor (Pan)
HRAS Q61C PIK3CG inhibitor
HRAS G12V PIK3CD inhibitor
HRAS G12C PIK3CG inhibitor
HRAS D33N PIK3CB inhibitor
HRAS Q61L PIK3CG inhibitor
HRAS G12D PIK3CG inhibitor
HRAS G12N PIK3CB inhibitor
HRAS G12F PIK3CG inhibitor
HRAS G13X PIK3CB inhibitor
HRAS Q61V PIK3CB inhibitor
HRAS G12K PIK3CB inhibitor
HRAS G13V PIK3CB inhibitor
HRAS Q61N PIK3CA inhibitor
HRAS Q61I PIK3CB inhibitor
HRAS G13D PIK3CG inhibitor
HRAS A146T PIK3CG inhibitor
HRAS G12I PIK3CA inhibitor
HRAS G13R PI3K Inhibitor (Pan)
HRAS K117E PI3K Inhibitor (Pan)
HRAS Q61H PIK3CD inhibitor
HRAS D33N PIK3CG inhibitor
HRAS G12F PI3K Inhibitor (Pan)
HRAS Q61R PIK3CD inhibitor
HRAS G12X PIK3CD inhibitor
HRAS inact mut PIK3CB inhibitor
HRAS Q61W PIK3CD inhibitor
HRAS G13R PIK3CG inhibitor
HRAS G12M PIK3CD inhibitor
HRAS G12L PIK3CA inhibitor
HRAS Q61X PI3K Inhibitor (Pan)
HRAS inact mut PI3K Inhibitor (Pan)
HRAS G12K PIK3CD inhibitor
HRAS G12Y PIK3CD inhibitor
HRAS G13I PI3K Inhibitor (Pan)
HRAS K117N PIK3CA inhibitor
HRAS G13C PI3K Inhibitor (Pan)
HRAS Q61T PIK3CD inhibitor
HRAS G12A PI3K Inhibitor (Pan)
HRAS G12A PIK3CD inhibitor
HRAS G13V PIK3CD inhibitor
HRAS G13D PIK3CA inhibitor
HRAS G13X PI3K Inhibitor (Pan)
HRAS G12T PIK3CG inhibitor
HRAS G12X PIK3CB inhibitor
HRAS G12H PIK3CA inhibitor
HRAS Q61E PIK3CA inhibitor
HRAS Q61A PIK3CB inhibitor
HRAS G12I PIK3CB inhibitor
HRAS G12W PI3K Inhibitor (Pan)
HRAS Q61T PI3K Inhibitor (Pan)
HRAS G12Q PIK3CB inhibitor
HRAS G12R PIK3CB inhibitor
HRAS A146V PIK3CD inhibitor
HRAS G13T PIK3CB inhibitor
HRAS Q61V PIK3CG inhibitor
HRAS A146T PIK3CD inhibitor
HRAS Q61X PIK3CG inhibitor
HRAS G12I PIK3CG inhibitor
HRAS G12H PIK3CD inhibitor
HRAS D33N PIK3CD inhibitor
HRAS Q61P PIK3CG inhibitor
HRAS G12M PIK3CG inhibitor
HRAS G13I PIK3CD inhibitor
HRAS Q61W PIK3CA inhibitor
HRAS Q61C PIK3CD inhibitor
HRAS G12S PIK3CA inhibitor
HRAS K117E PIK3CA inhibitor
HRAS Q61X PIK3CA inhibitor
HRAS Q61H PIK3CG inhibitor
HRAS G13S PIK3CD inhibitor
HRAS G12I PI3K Inhibitor (Pan)
HRAS G12E PIK3CA inhibitor
HRAS Q61I PIK3CG inhibitor
HRAS Q61X PIK3CD inhibitor
HRAS A146T PIK3CB inhibitor
HRAS G12E PIK3CB inhibitor
HRAS G13D PIK3CD inhibitor
HRAS G13V PIK3CA inhibitor
HRAS G12W PIK3CB inhibitor
HRAS K117N PI3K Inhibitor (Pan)
HRAS K117E PIK3CG inhibitor
HRAS G12K PIK3CG inhibitor
HRAS G12T PIK3CB inhibitor
HRAS Q61M PIK3CB inhibitor
HRAS G12F PIK3CB inhibitor
HRAS G12E PI3K Inhibitor (Pan)
HRAS G12Q PIK3CG inhibitor
HRAS Q61P PIK3CA inhibitor
HRAS Q61Y PI3K Inhibitor (Pan)
HRAS D33N PIK3CA inhibitor
HRAS G12X PIK3CG inhibitor
HRAS G12I PIK3CD inhibitor
HRAS G13X PIK3CD inhibitor
HRAS G12N PI3K Inhibitor (Pan)
HRAS G12V PIK3CA inhibitor
HRAS Q61P PIK3CB inhibitor
HRAS Q61F PIK3CG inhibitor
HRAS Q61Y PIK3CB inhibitor
HRAS Q61N PIK3CB inhibitor
HRAS Q61F PI3K Inhibitor (Pan)
HRAS G13S PIK3CG inhibitor
HRAS G12T PIK3CD inhibitor
HRAS G12N PIK3CA inhibitor
HRAS G12H PIK3CB inhibitor
HRAS G13V PI3K Inhibitor (Pan)
HRAS G12N PIK3CG inhibitor
HRAS inact mut PIK3CG inhibitor
HRAS G12F PIK3CD inhibitor
HRAS G13R PIK3CD inhibitor
HRAS Q61L PIK3CA inhibitor
HRAS Q61K PIK3CD inhibitor
HRAS G12E PIK3CG inhibitor
HRAS G12E PIK3CD inhibitor
HRAS Q61R PIK3CA inhibitor
HRAS G12Q PI3K Inhibitor (Pan)
HRAS G12L PIK3CB inhibitor
HRAS G12S PI3K Inhibitor (Pan)
HRAS Q61R PIK3CB inhibitor
HRAS Q61K PIK3CG inhibitor
HRAS G13S PI3K Inhibitor (Pan)
HRAS G12K PI3K Inhibitor (Pan)
HRAS Q61G PIK3CD inhibitor
HRAS G12A PIK3CG inhibitor
HRAS T58I PIK3CA inhibitor
HRAS G12W PIK3CD inhibitor
HRAS G12C PIK3CD inhibitor
HRAS G12L PI3K Inhibitor (Pan)
HRAS G13T PI3K Inhibitor (Pan)
HRAS A146V PIK3CA inhibitor
HRAS G12L PIK3CD inhibitor
HRAS G13S PIK3CA inhibitor
HRAS K117R PIK3CA inhibitor
HRAS Q61R PI3K Inhibitor (Pan)
HRAS G13C PIK3CB inhibitor
HRAS Q61N PIK3CG inhibitor
HRAS Q61L PIK3CB inhibitor
HRAS G13X PIK3CG inhibitor
HRAS Q61E PIK3CB inhibitor
HRAS Q61A PIK3CA inhibitor
HRAS G12L PIK3CG inhibitor
HRAS G13T PIK3CA inhibitor
HRAS Q61C PI3K Inhibitor (Pan)
HRAS Q61Y PIK3CA inhibitor
HRAS Q61P PI3K Inhibitor (Pan)
HRAS Q61H PIK3CB inhibitor
HRAS G12Y PIK3CA inhibitor
HRAS Q61A PIK3CG inhibitor
HRAS Q61Y PIK3CD inhibitor
HRAS Q61Y PIK3CG inhibitor
HRAS Q61E PIK3CG inhibitor
HRAS G13S PIK3CB inhibitor
HRAS Q61V PIK3CD inhibitor
HRAS G12C PI3K Inhibitor (Pan)
HRAS G12X PIK3CA inhibitor
HRAS A146V PIK3CG inhibitor
HRAS K117E PIK3CD inhibitor
HRAS G13R PIK3CA inhibitor
HRAS G12S PIK3CB inhibitor
HRAS G13T PIK3CG inhibitor
HRAS Q61T PIK3CG inhibitor
HRAS Q61H PI3K Inhibitor (Pan)
HRAS inact mut PIK3CD inhibitor
HRAS G12D PIK3CA inhibitor
HRAS inact mut PIK3CA inhibitor
HRAS G12N PIK3CD inhibitor
HRAS Q61C PIK3CB inhibitor
HRAS T58I PIK3CG inhibitor
HRAS G12K PIK3CA inhibitor
HRAS Q61F PIK3CB inhibitor
HRAS Q61V PIK3CA inhibitor
HRAS Q61T PIK3CB inhibitor
HRAS A146V PI3K Inhibitor (Pan)
HRAS A59T PI3K Inhibitor (Pan)
HRAS G12F PIK3CA inhibitor
HRAS G12Y PI3K Inhibitor (Pan)
HRAS G12Y PIK3CG inhibitor
HRAS G13R PIK3CB inhibitor
HRAS Q61W PIK3CB inhibitor
HRAS G12V PIK3CG inhibitor
HRAS Q61I PIK3CD inhibitor
HRAS Q61A PIK3CD inhibitor
HRAS Q61N PIK3CD inhibitor
HRAS G12D PIK3CD inhibitor
HRAS Q61G PIK3CG inhibitor
HRAS A146T PI3K Inhibitor (Pan)
HRAS D33N PI3K Inhibitor (Pan)
HRAS Q61M PI3K Inhibitor (Pan)
HRAS Q61E PI3K Inhibitor (Pan)
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
HRAS inact mut thyroid gland cancer sensitive Dactolisib Preclinical Actionable In a preclinical study, BEZ235 inhibited growth of thyroid cancer cells harboring an HRAS pathway activating mutation in cell culture (PMID: 21831957). 21831957