Big cells, bigger BTK resistance in mantle cell lymphoma

In this issue of Blood, Wang et al 1 have identified drug-tolerant persister cells, which they call giant cells, in patients with mantle cell lymphoma (MCL) receiving the noncovalent Bruton tyrosine kinase (BTK) inhibitor pirtobrutinib.Using xenografts and organoids derived from patients with MCL, they found that these giant cells were also present upon treatment with covalent BTK inhibitors, venetoclax, and an anti-ROR1 monoclonal antibody, suggesting a more generalizable resistance mechanism.When the drugs were removed from the system, the cells returned to their usual size and proliferated (see figure).This change in cell size in response to drug exposure is potentially regulated by a metabolic switch in the tricarboxylic acid cycle.Acetyl coenzyme A (acetyl-CoA) controls this switch and could be modulated by inhibiting adenosine triphosphate-citrate lyase (ACL), an enzyme that produces acetyl-CoA from citrate.In addition, there was a shift of the malate-aspartate shuttle activity between the mitochondria and cytoplasm in the giant cells that was dependent on the expression of GOT2, the gene that encodes glutamate-oxaloacetate transaminase 2.