Researchers Uncover Mechanisms of BH3 Mimetic Resistance in T-Cell ALL

By Cecilia Brown - Last Updated: August 29, 2023

Combining BH3 mimetics with tyrosine kinase inhibitors (TKIs) “might be effective” against relapsed T-cell acute lymphoblastic leukemia (ALL), according to a recent study.

Caner Saygin, MD, of the University of Chicago, and colleagues conducted the research because relapsed T-cell ALL has “limited treatment options.”

They studied mechanisms of resistance to BH3 mimetics to “develop rational combination strategies” and evaluated the preclinical efficacy of NWP-0476, a novel BCL-2/BCL-xL inhibitor, in T-cell ALL.

Dr. Saygin and colleagues used BH3 profiling to predict responses to BH3 mimetics in T-cell ALL. They used isogeneic control and a phosphokinase array to identify differentially regulated signaling pathways in venetoclax-resistant cells and cells that were resistant to NWP-0476.

Study Evaluates BCL-2, BCL-xL Inhibition in T-cell ALL

The researchers found that “typical” T-cell ALL cells showed increased dependence upon BCL-xL. However, early T-precursor ALL cells showed a higher dependence on BCL-2 for survival. Dual inhibitors of BCL-2 and BCL-xL were found to be “effective against both subtypes of T-lineage ALL,” according to Dr. Saygin and colleagues.

The 71-protein human phosphokinase array showed increased LCK activity in venetoclax-resistant cells. It showed increased ACK1 activity in venetoclax-resistant cells and cells that were resistant to NWP-0476.

Dr. Saygin and colleagues hypothesized that pre-T-cell receptor signaling pathways are drivers of resistance to BCL-2 inhibition and that ACK1 signaling pathways are drivers of resistance to BCL-xL inhibition.

They first silenced the LCK gene in T-cell ALL cell lines and found that silencing LCK led to increased sensitivity to BCL-2 inhibition.

“Mechanistically, LCK activated [the] NF-κB pathway and the expression of BCL-xL,” Dr. Saygin and colleagues wrote.

Silencing the ACK1 gene led to increased sensitivity of BCL-2 inhibitors and BCL-xL inhibitors. They found that ACK1 signaling upregulated the AKT pathway, inhibiting the proapoptotic function of BAD.

Dr. Saygin and colleagues evaluated the combination of NWP-0476 and dasatinib in a T-cell ALL patient-derived xenograft model and found the two drugs “demonstrated synergy without major organ toxicity.”

Based on the results, the study’s investigators concluded that LCK and ACK1 signaling pathways are “critical regulators of BH3 mimetic resistance” in T-cell ALL and combining BH3 mimetics with TKIs “might be effective against relapsed T-cell ALL.”

Reference

Saygin C, Giordano G, Shimamoto K, et al. Dual targeting of apoptotic and signaling pathways in T-lineage acute lymphoblastic leukemia. Clin Cancer Res. 2023;29(16):3151-3161. doi:10.1158/1078-0432.ccr-23-0415

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