Drug degrader targets MYC in resistant blood-cancer models

At The University of Texas MD Anderson Cancer Center, researchers are attacking a protein that cancer biologists have spent decades trying to block. Their experimental drug GT19630 showed anticancer activity in preclinical models of leukemia, lymphoma and multiple myeloma, including treatment-resistant disease and cancers with TP53 mutations.

The target is MYC, a protein involved in approximately 70% of all human cancers. It acts as a master switch for genes that help cancer cells grow, divide and sustain their metabolism. The difficulty has been finding a way to interfere with it effectively. Michael Andreeff and Yuki Nishida’s team found that MYC activates the GSPT1 gene, while GSPT1 helps cancer cells produce MYC: a self-reinforcing loop.

GT19630 breaks that loop. The protein degrader binds MYC and GSPT1, then marks MYC for destruction by the cell’s natural protein-recycling system while degrading GSPT1 as well. In models of acute myeloid leukemia, or AML, cells resistant to venetoclax had increased levels of both proteins; GT19630 restored venetoclax sensitivity and prolonged survival by more than 300% in one model.

The result could matter most for patients whose leukemia survives initial treatment. Single-cell RNA analysis found elevated MYC in TP53-mutant AML stem cells, which can contribute to relapse, while normal blood-forming stem cells were less affected in the experiments. That suggests a possible therapeutic window, though it does not yet establish how the drug will behave in people.

And then, concretely? GT19630 is not a treatment available to patients: it is a preclinical candidate. Its immediate value is to give researchers a route toward MYC-driven blood cancers, including venetoclax-resistant or relapsed AML, and a possible biomarker strategy for identifying tumors most likely to respond. The next studies must determine whether the selective effect survives testing in patients and whether GT19630 works alone or alongside other therapies.