Emerging Agents for the Treatment of Advanced, Imatinib-Resistant Gastrointestinal Stromal Tumors : Current Status and Future Directions

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http://hdl.handle.net/10138/212223

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Bauer , S & Joensuu , H 2015 , ' Emerging Agents for the Treatment of Advanced, Imatinib-Resistant Gastrointestinal Stromal Tumors : Current Status and Future Directions ' , Drugs , vol. 75 , no. 12 , pp. 1323-1334 . https://doi.org/10.1007/s40265-015-0440-8

Titel: Emerging Agents for the Treatment of Advanced, Imatinib-Resistant Gastrointestinal Stromal Tumors : Current Status and Future Directions
Författare: Bauer, Sebastian; Joensuu, Heikki
Upphovmannens organisation: Clinicum
Heikki Joensuu / Principal Investigator
Department of Oncology
Datum: 2015-08
Språk: eng
Sidantal: 12
Tillhör serie: Drugs
ISSN: 0012-6667
DOI: https://doi.org/10.1007/s40265-015-0440-8
Permanenta länken (URI): http://hdl.handle.net/10138/212223
Abstrakt: Imatinib is strongly positioned as the recommended first-line agent for most patients with advanced gastrointestinal stromal tumor (GIST) due to its good efficacy and tolerability. Imatinib-resistant advanced GIST continues to pose a therapeutic challenge, likely due to the frequent presence of multiple mutations that confer drug resistance. Sunitinib and regorafenib are approved as second- and third-line agents, respectively, for patients whose GIST does not respond to imatinib or who do not tolerate imatinib, and their use is supported by large randomized trials. ATP-mimetic tyrosine kinase inhibitors provide clinical benefit even in heavily pretreated GIST suggesting that oncogenic dependency on KIT frequently persists. Several potentially useful tyrosine kinase inhibitors with distinct inhibitory profiles against both KIT ATP-binding domain and activation loop mutations have not yet been fully evaluated. Agents that have been found promising in preclinical models and early clinical trials include small molecule KIT and PDGFRA mutation-specific inhibitors, heat shock protein inhibitors, histone deacetylase inhibitors, allosteric KIT inhibitors, KIT and PDGFRA signaling pathway inhibitors, and immunological approaches including antibody-drug conjugates. Concomitant or sequential administration of tyrosine kinase inhibitors with KIT signaling pathway inhibitors require further evaluation, as well as rotation of tyrosine kinase inhibitors as a means to suppress drug-resistant cell clones.
Subject: KIT TYROSINE KINASE
PHASE-II
C-KIT
HSP90 INHIBITOR
PROGNOSTIC-FACTORS
ADJUVANT IMATINIB
RANDOMIZED-TRIAL
DRUG-RESISTANCE
BRAF MUTATIONS
DOSE IMATINIB
3122 Cancers
317 Pharmacy
Referentgranskad: Ja
Licens: cc_by
Användningsbegränsning: openAccess
Parallelpublicerad version: publishedVersion


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