Functional Testing to Characterize and Stratify PI3K Inhibitor Responses in Chronic Lymphocytic Leukemia

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Phosphoinositide 3-kinase inhibitors (PI3Ki) are approved for treating chronic lymphocytic leukemia (CLL).
• Treatment intolerance and resistance to PI3Ki present significant clinical challenges in CLL management.
• Predictive biomarkers are crucial for optimizing individual treatment responses to PI3Ki therapies.

Purpose of the Study:

• To characterize the activity and cellular effects of 10 PI3Ki in CLL.
• To identify treatment vulnerabilities in PI3Ki-refractory/intolerant CLL using functional analyses.
• To determine if ex vivo functional profiling can stratify patients who will respond to PI3Ki.

Main Methods:

• Peripheral blood mononuclear cells from 51 treatment-naïve and PI3Ki-treated CLL patients were analyzed.
• Cells were profiled against 10 PI3Ki and venetoclax using flow cytometry for signaling and immune phenotypes.
• Cell viability was assessed via cleaved caspase-3 and CellTiter-Glo assays; drug sensitivities and protein profiling were also performed.

Main Results:

• Pan-PI3Ki demonstrated efficacy in inhibiting PI3K signaling and viability in both treatment-naïve and idelalisib-refractory/intolerant CLL cells.
• Copanlisib, a pan-PI3Ki, inhibited PI3K signaling in B and T cells, unlike idelalisib.
• Combination therapy with PI3Ki and venetoclax synergistically induced apoptosis; drug sensitivity analysis stratified responders.

Conclusions:

• Novel treatment vulnerabilities in idelalisib-refractory/intolerant CLL were identified.
• Ex vivo functional profiling shows promise for stratifying patients likely to respond to PI3Ki.
• These findings support the development of personalized treatment strategies for CLL.