DOES RESISTANCE IN GIST DEMAND A DIFFERENT APPROACH?
GIST is fueled by a myriad of mutations that play a key role in1-3:
- Unregulated kinase activity
- Mechanisms of resistance
A different approach may be needed to2-5:
- Overcome resistance
- Control disease progression
- Provide patients, caregivers, and physicians with additional treatment options
STAY UP-TO-DATE ON THE EMERGING SCIENCE IN GIST
Get startedA MYRIAD OF MUTATIONS FUEL RESISTANCE AND PROGRESSION,
RESULTING IN UNREGULATED KINASE ACTIVITY2,3
GIST is most often fueled by activating mutations in kinase genes6:
KIT
70-80% OF CASES
PDGFRα
5-10% OF CASES
THESE KIT AND PDGFRα MUTATIONS KEEP THE KINASE IN THE ACTIVE STATE,
CAUSING UNCONTROLLED CELL PROLIFERATION AND/OR CELL SURVIVAL.7,8
The complexity of GIST is further complicated by2,9,10:
Broad intra- and
inter-tumor heterogeneity
Multiple evolving
resistance mutations
A single patient with GIST may have multiple mutations within or between tumors, contributing to resistance and disease progression.8
LEARN MORE ABOUT THE COMPLEX MUTATIONS DRIVING GIST
Get startedSIGNIFICANT UNMET NEEDS REMAIN IN ADVANCED GIST3
TKI therapy is the standard of care for patients with recurrent or unresectable GIST. However, the vast majority of patients who respond to front-line treatment with imatinib will eventually develop resistance.6
CURRENT TKIs ARE UNABLE TO FULLY REGULATE KINASE ACTIVITY1,8
First-generation TKIs in GIST bind to the inactive state of the kinase via the ATP binding site.1,10
However, as resistance mutations develop, these inhibitors may lose their ability to prevent kinase activation, leading to cell proliferation.1,10
TOLERABILITY ISSUES ADD TO THE BURDEN OF DISEASE5,11-13
As GIST progresses, patients may face not only an increased disease burden, but also tolerability challenges presented by second- and third-line TKIs. AEs associated with current treatments may lead to dose modifications, including reductions or interruptions. Effective management of AEs may help maintain adequate dosing and continuation of treatment.5,11-13
AE=adverse events; TKI=tyrosine kinase inhibitor.
STAY UP-TO-DATE ON CLINICAL ADVANCES IN GIST
Get startedSWITCH CONTROL IS A PROMISING APPROACH TO TARGETING THE
DRIVERS OF RESISTANCE AND PROGRESSION IN ADVANCED GIST4
Given the myriad of mutations that fuel drug resistance and progression in GIST, is there a need for a different therapeutic approach that broadly inhibit KIT and PDGRa mutations?4
Switch control involves targeting the kinase in two ways1,4:
- Preventing the activation loop from binding to the switch pocket
- Locking the kinase in the inactive (“off”) state
This unique approach has the potential to4:
- Regulate kinase activity
- Inhibit a broader spectrum of KIT and PDGFRα mutations driving GIST
Achieving switch control may prevent downstream signaling and cell proliferation, and potentially overcome the mechanisms of resistance associated with advanced GIST1,4
LEARN MORE ABOUT NEW RESEARCH IN ADVANCED GIST
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