Impact of PIK3CA gain and PTEN loss on mantle cell lymphoma biology and sensitivity to targeted therapies

Abstract

ABSTRACTBesides many other mutations in known cancer driver genes, mantle cell lymphoma (MCL) is characterized by recurrent genetic alterations of important regulators of the phosphoinositol-3-kinase (PI3K) cascade includingPIK3CAgains andPTENlosses. To evaluate the biological and functional consequences of these aberrations in MCL, we have introduced transgenic expression ofPIK3CA(PIK3CA UP) and performed knockout ofPTENgene (PTEN KO) in 5 MCL cell lines. The modified cell lines were tested for associated phenotypes including dependence on upstream B-cell receptor (BCR) signaling (by an additionalBCRknockout). PIK3CA overexpression decreased the dependence of the tested MCL on prosurvival signaling from BCR, decreased levels of oxidative phosphorylation, and increased resistance to 2-deoxy-glucose, a glycolysis inhibitor. Unchanged AKT phosphorylation status and unchanged sensitivity to a battery of PI3K inhibitors suggested thatPIK3CAgain might impact MCL cells in AKT independent manner.PTENKO was associated with a more distinct phenotype: AKT hyperphosphorylation and overactivation, increased resistance to multiple inhibitors (most of the tested PI3K inhibitors, BTK inhibitor ibrutinib, and BCL2 inhibitor venetoclax), increased glycolytic rates with resistance to 2-deoxy-glucose, and significantly decreased dependence on prosurvival BCR signaling. Our results suggest that the frequent aberrations of the PI3K pathway may rewire associated signaling with lower dependence on BCR signaling, better metabolic and hypoxic adaptation, and targeted therapy resistance in MCL.Key point 1PIK3CA gain and PTEN loss decrease the dependence of MCL cells on B-Cell Receptor Signaling and anti-apoptotic BCL2.Key point 2PIK3CA gain and PTEN loss lead to complex metabolic rewiring and increased survival of MCL cells under hypoxia.