ArticleClinical cancer research : an official journal of the American Association for Cancer Research2022
Functional Testing to Characterize and Stratify PI3K Inhibitor Responses in Chronic Lymphocytic Leukemia.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 11 citations in OpenAlex.
- Protein Profiles Predict Treatment Responses to the PI3K Inhibitor Umbralisib in Patients with Chronic Lymphocytic Leukemia.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Trial
- Article
- Evolution of the drug sensitivity landscape of chronic lymphocytic leukaemia.British journal of haematology · 2026Article
- Proteasome inhibition overcomes resistance to targeted therapies in B-cell malignancy models and in an index patient.Cell death & disease · 2025Article
- PI3K Inhibitors in Hematology: When One Door Closes….Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Review
- Immunophenotyping with (phospho)protein profiling and fluorescent cell barcoding for single-cell signaling analysis and biomarker discovery.NPJ precision oncology · 2024Review
- Robust scoring of selective drug responses for patient-tailored therapy selection.Nature protocols · 2024Review
- Standardized assays to monitor drug sensitivity in hematologic cancers.Cell death discovery · 2023Article
- Functional impact and molecular binding modes of drugs that target the PI3K isoform p110δ.Communications biology · 2023Article
- A tumor microenvironment model of chronic lymphocytic leukemia enables drug sensitivity testing to guide precision medicine.Cell death discovery · 2023Article
- PI3K inhibitors in chronic lymphocytic leukemia: where do we go from here?Haematologica · 2023Review
- Mutational analysis and protein profiling predict drug sensitivity in multiple myeloma cell lines.Frontiers in oncology · 2022Article
Corrections and comments
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Authors and funding
17 authors at 8 institutions in 4 countries.
Funding
Abstract
purposePI3K inhibitors (PI3Ki) are approved for relapsed chronic lymphocytic leukemia (CLL). Although patients may show an initial response to these therapies, development of treatment intolerance or resistance remain clinical challenges. To overcome these, prediction of individual treatment responses based on actionable biomarkers is needed. Here, we characterized the activity and cellular effects of 10 PI3Ki and investigated whether functional analyses can identify treatment vulnerabilities in PI3Ki-refractory/intolerant CLL and stratify responders to PI3Ki. EXPERIMENTAL
designPeripheral blood mononuclear cell samples (n = 51 in total) from treatment-naïve and PI3Ki-treated patients with CLL were studied. Cells were profiled against 10 PI3Ki and the Bcl-2 antagonist venetoclax. Cell signaling and immune phenotypes were analyzed by flow cytometry. Cell viability was monitored by detection of cleaved caspase-3 and the CellTiter-Glo assay.
resultspan-PI3Kis were most effective at inhibiting PI3K signaling and cell viability, and showed activity in CLL cells from both treatment-naïve and idelalisib-refractory/intolerant patients. CLL cells from idelalisib-refractory/intolerant patients showed overall reduced protein phosphorylation levels. The pan-PI3Ki copanlisib, but not the p110δ inhibitor idelalisib, inhibited PI3K signaling in CD4+ and CD8+ T cells in addition to CD19+ B cells, but did not significantly affect T-cell numbers. Combination treatment with a PI3Ki and venetoclax resulted in synergistic induction of apoptosis. Analysis of drug sensitivities to 73 drug combinations and profiling of 31 proteins stratified responders to idelalisib and umbralisib, respectively.
conclusionsOur findings suggest novel treatment vulnerabilities in idelalisib-refractory/intolerant CLL, and indicate that ex vivo functional profiling may stratify PI3Ki responders.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.