GAB1 inhibitors may be effective against chronic lymphocytic leukemia (CLL), particularly when combined with ibrutinib, preclinical research suggests. The findings were recently published in Blood.
Researchers found that GAB1 inhibitors can induce apoptosis in CLL cells and impair CLL cell migration.
To better understand CLL cell migration, the researchers evaluated 2 subpopulations of cells — CXCR4brightCD5dim, which represent cells that circulate in the peripheral blood for an extended time before returning to immune niches, and CXCR4dimCD5bright, which represent cells that have recently exited the microenvironment.
Experiments revealed higher levels of GAB1 in the cells ready to migrate back to immune niches. This GAB1 accumulation was mediated by FoxO1-based transcriptional GAB1 activation.
Higher levels of GAB1 and FoxO1 in the cells ready to migrate to immune niches contributed to “tonic” AKT phosphorylation. An accumulation of FoxO1 and GAB1 was also observed when MEC1 cells were exposed to ibrutinib.
GAB1 inhibitors (GAB1-001 and GAB1-004) impaired CLL cell migration and induced apoptosis in CLL cells. When CLL cells were exposed to GAB1 inhibitors and ibrutinib in combination, apoptosis was significantly greater than when any of the agents was used alone (P < .001).
“We have demonstrated that GAB1 can be targeted therapeutically by novel GAB1 inhibitors alone or in combination with BTK inhibition,” the researchers concluded. “GAB1 inhibitors induce CLL cell apoptosis, impair cell migration, inhibit ‘tonic’ or BCR-induced AKT phosphorylation, and block compensatory AKT activity during ibrutinib therapy.”
Disclosures: This research was supported by the Czech Science Foundation and other organizations. The study authors declared no competing interests. Please see the original reference for a full list of funding sources.
Seda V, Vojackova E, Ondrisova L, et al. FoxO1-GAB1 Axis Regulates Homing Capacity and Tonic AKT Activity in Chronic Lymphocytic Leukemia. Blood. Published online March 30, 2021. doi:10.1182/blood.2020008101