Addressing Resistance and Rare Subsets in GIST

Neeta Somaiah, MD, professor and department chair in the department of sarcoma medical oncology in the division of cancer medicine at The University of Texas MD Anderson Cancer Center in Houston, Texas, summarized the promising areas of investigation into gastrointestinal stromal cancer (GIST) that she presented on at the 4th Annual Miami Cancer Institute Precision Oncology Symposium on January 30 to 31, 2026. She identified 2 primary frontiers for clinical investigation: the eradication of persistent cancer cells and the management of increasingly complex resistance mutations.

The Challenge of Cellular Persistence

Somaiah noted that a significant looming question in GIST treatment is that some cells persist and develop resistance to treatment even when patients exhibit a robust initial response to treatment. These cells act as a reservoir for future disease progression, as they are inherently prone to developing secondary resistance over time. Somaiah suggested that future drug development must prioritize finding ways to kill the residual cells that survive initial kinase inhibition as well as intervening proactively to address these cells before they have the opportunity to mutate further.

The Shift in Resistance Patterns

As more potent and broader-spectrum drugs are moved into frontline treatment settings, Somaiah warned of a shift in the mutational landscape. Although these drugs improve initial outcomes, the resistance mutations that eventually emerge may be more challenging to treat. The concern is that subsequent mutations might be unresponsive to the current arsenal of available inhibitors, necessitating a new wave of drug development focused specifically on these late-developing alterations.

Prioritizing Underserved Patient Subsets

Beyond common mutational profiles, the speaker emphasized the urgent need for research into rare GIST subsets, which have historically been underserved. The subset of SDH-deficient GIST does not typically respond to standard tyrosine kinase inhibitors. However, Somaiah highlighted promising activity from FGFR inhibitors, with hopes for upcoming grant-funded clinical trials. NF1-related GIST is another rare group that presents unique therapeutic hurdles.

Somaiah concluded by noting that while it is difficult to gather support for testing drugs in such small populations, collaborative efforts between specialized sarcoma institutions are essential for moving the needle on these rare and difficult-to-treat tumors.