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Use of ponatinib to inhibit kinase mutations associated with drug-resistant gastrointestinal stromal tumors (GIST).
J Clin Oncol 31, 2013 (suppl; abstr 10509)
Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).
Background: Ponatinib (PO) is a multi-targeted tyrosine kinase inhibitor with potent pan-BCR-ABL activity that has recently been approved for treatment of CML and Ph+ ALL. PO also inhibits the kinase activity of KIT. Approximately 80% of gastrointestinal stromal tumors (GIST) contain primary activating KIT mutations, the majority of which cluster in exon 11. Imatinib (IM) is approved for the 1st line treatment of GIST; however, patients frequently relapse due to the acquisition of secondary resistance mutations located in either the KIT ATP-binding pocket or the activation (A) loop. Sunitinib (SU) is approved for 2nd line treatment of GIST but does not effectively inhibit A-loop mutants. Here we explored the activity of PO against major primary and secondary KIT mutants found in GIST. Methods: The drug sensitivity of KIT mutants was determined using engineered Ba/F3 cells harboring mutant forms of KIT exon 11 with or without ATP binding pocket or A-loop mutations. The abilities of PO, IM, SU, and regorafenib (RE) to inhibit viability and/or KIT kinase activity were compared using this system as well as an isogenic CHO cell system. We also profiled these same drugs using a panel of GIST cell lines, including cell lines with IM-resistant secondary KIT mutations. Results: In all in vitro systems, PO potently inhibited KIT exon 11 mutant kinases, with an IC50 of < 30 nM. PO also potently inhibited a range of secondary KIT mutants, including multiple A-loop mutant kinases. PO induced substantial tumor regression in Ba/F3 tumor models expressing a KIT exon 11 mutant with or without an A-loop mutation (D816H). Using GIST cell lines, PO inhibited the viability of those harboring primary KIT exon 11 and secondary resistance mutations more effectively than IM, SU, and RE. Importantly, in patients dosed once daily with 45 mg ponatinib, plasma concentrations achieved are predicted to lead to inhibition of all KIT mutants tested with the possible exception of V654A. Conclusions: PO potently inhibits the majority of clinically relevant KIT mutant kinases and has a broader spectrum of activity compared to IM, SU, or RE. Based on these data, a phase 2 study of PO in drug-resistant GIST is being initiated.
Abstracts by M. C. Heinrich:
Meeting: 2013 Genitourinary Cancers Symposium
| Abstract No: 80
Category: Genitourinary Cancer - Prostate Cancer
In vitro and in vivo activity of regorafenib (REGO) in drug-resistant gastrointestinal stromal tumors (GIST).Category: Sarcoma - GIST
Prolonged survival and disease control in the academic phase II trial of regorafenib in GIST: Response based on genotype.Category: Sarcoma - GIST
Educational Book Articles by M. C. Heinrich:
Source: 2012 Educational Book
Source: 2010 Educational Book
Optimizing the Treatment of Gastrointestinal Stromal Tumors: The Roles of Tumor Genotyping, Imatinib Blood-level Testing, and New Therapeutic StrategiesCategory: Sarcoma/Bone and Soft Tissue Cancers
Presentations by M. C. Heinrich:
Meeting: 2012 ASCO Annual Meeting
Session: What the Busy Oncologist Needs to Know about Gastrointestinal Stromal Tumor (Education Session)
The effect of crenolanib (CP-868,596) on phosphorylation of the imatinib-resistant D842V PDGFRA activating mutation associated with advanced gastrointestinal stromal tumors.Session: Sarcoma (Poster Discussion Session)
In vitro activity of novel KIT/PDGFRA switch pocket kinase inhibitors against mutations associated with drug-resistant GI stromal tumors.Session: Sarcoma (Oral Abstract Session)