PIK3CA Gains and PTEN Losses Shape Therapeutic Response in Mantle Cell Lymphoma
Mantle cell lymphoma (MCL), a B-cell non-Hodgkin lymphoma, is characterized by recurrent genetic alterations in key regulators of the phosphoinositide-3-kinase (PI3K) pathway, including PIK3CA gains and PTEN losses. A recent study published in Blood Advances explored the biological and functional consequences of these aberrations in MCL using transgenic PIK3CA expression and PTEN knockout/knockdown models in 5 MCL cell lines to shed light on what these alterations mean for progression and therapeutic resistance.
PIK3A gains and PTEN deletions were prevalent in patients with MCL samples, with 43% showing PIK3CA gains and 7% exhibiting PTEN deletions. PIK3CA overexpression resulted in decreased reliance on B-cell receptor (BCR) signaling for survival, reduced oxidative phosphorylation, and increased resistance to glycolysis inhibition. These effects appeared to operate independently of protein kinase B (AKT) activation, as PIK3CA gain did not significantly alter AKT phosphorylation or activity. The reduced dependence on BCR signaling and enhanced metabolic flexibility provided by PIK3CA gain may support MCL cell survival.
In contrast, PTEN loss led to pronounced AKT hyperactivation, marked resistance to multiple inhibitors, including PI3K, Bruton tyrosine kinase (BTK), and BCL2 inhibitors, and increased glycolytic activity. These effects were accompanied by a substantial decrease in reliance on BCR signaling, indicating a rewired survival mechanism. PTEN loss also supported metabolic reprogramming. Unlike PIK3CA gain, the AKT hyperactivation associated with PTEN loss made cells more resistant to targeted therapies but left them sensitive to AKT inhibitors and certain BCL-XL inhibitors.
Both PIK3CA gains and PTEN losses contributed to resistance against PI3K inhibitors, with PTEN loss showing a more substantial impact. Resistance to BTK inhibitors, such as ibrutinib, was more pronounced in PTEN-deficient cells, highlighting the potential of PTEN as a predictive biomarker for BTK inhibitor sensitivity. The study also demonstrated altered responses to BH3 mimetics, with PTEN losses increasing resistance to venetoclax but enhancing sensitivity to BCL-XL inhibitors. These findings underscore the need to tailor therapeutic strategies based on the specific PI3K pathway alteration present in MCL.
“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,” the researchers concluded.
Reference
Bettazova N, Senavova J, Kupcova K, et al. Impact of PIK3CA gain and PTEN loss on mantle cell lymphoma biology and sensitivity to targeted therapies. Blood Adv. 2024;8(20):5279-5289. doi:10.1182/bloodadvances.2024013205
