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Phosphoproteomics Identifies PI3K Inhibitor-selective Adaptive Responses in Pancreatic Cancer Cell Therapy and
Célia Cintas1,2, Thibault Douche1,2, Zahra Dantes3,4,5
1INSERM, CNRS, Université Paul Sabatier, U1037, CRCT, Toulouse, France.
Abstract:
The PI3K pathway is highly active in human cancers. The four class I isoforms of PI3K are activated by distinct mechanisms leading to a common downstream signaling. Their downstream redundancy is thought to be responsible for treatment failures of PI3K inhibitors. We challenged this concept, by mapping the differential phosphoproteome evolution in response to PI3K inhibitors with different isoform-selectivity patterns in pancreatic cancer, a disease currently without effective therapy. In this cancer, the PI3K signal was shown to control cell proliferation. We compared the effects of LY294002 that inhibit with equal potency all class I isoenzymes and downstream mTOR with the action of inhibitors with higher isoform selectivity toward PI3Kα, PI3Kβ, or PI3Kγ (namely, A66, TGX-221 and AS-252424). A bioinformatics global pathway analysis of phosphoproteomics data allowed us to identify common and specific signals activated by PI3K inhibitors supported by the biological data. AS-252424 was the most effective treatment and induced apoptotic pathway activation as well as the highest changes in global phosphorylation-regulated cell signal. However, AS-252424 treatment induced reactivation of Akt, therefore decreasing the treatment outcome on cell survival. Reversely, AS-252424 and A66 combination treatment prevented p-Akt reactivation and led to synergistic action in cell lines and patient organoids. The combination of clinically approved α-selective BYL-719 with γ-selective IPI-549 was more efficient than single-molecule treatment on xenograft growth. Mapping unique adaptive signaling responses to isoform-selective PI3K inhibition will help to design better combinative treatments that prevent the induction of selective compensatory signals.
Insights
Targeting the PI3K pathway in pancreatic cancer requires understanding isoform-specific signaling. Combining isoform-selective PI3K inhibitors prevents resistance and enhances treatment efficacy, offering new therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- The phosphoinositide 3-kinase (PI3K) pathway is frequently hyperactivated in various human cancers, including pancreatic cancer.
- Distinct activation mechanisms of PI3K class I isoforms converge on common downstream signaling, leading to redundancy that compromises PI3K inhibitor effectiveness.
- Pancreatic cancer currently lacks effective therapeutic options, highlighting the need for novel treatment strategies targeting key signaling pathways like PI3K.
Purpose of the Study:
- To investigate the differential phosphoproteome dynamics in response to PI3K inhibitors with varying isoform selectivity in pancreatic cancer.
- To challenge the concept of PI3K pathway redundancy and identify unique adaptive signaling responses to isoform-selective inhibition.
- To explore combination therapies that overcome treatment resistance and improve therapeutic outcomes in pancreatic cancer.
Main Methods:
- Comparative phosphoproteomics analysis of pancreatic cancer cells treated with pan-PI3K inhibitors (LY294002) and isoform-selective inhibitors (A66, TGX-221, AS-252424).
- Bioinformatic global pathway analysis to identify common and specific signaling networks modulated by PI3K inhibitors.
- Evaluation of combination treatments using isoform-selective PI3K inhibitors in cell lines and patient-derived organoids, including assessment of xenograft tumor growth.
Main Results:
- AS-252424 (a PI3Kγ inhibitor) demonstrated the most potent anti-cancer effects, inducing apoptosis and significant global phosphoproteome changes, but also Akt reactivation.
- Combination of AS-252424 with A66 (a PI3Kα inhibitor) prevented Akt reactivation and exhibited synergistic effects in cell lines and organoids.
- Combination therapy with clinically relevant α-selective (BYL-719) and γ-selective (IPI-549) inhibitors showed superior efficacy against xenograft tumors compared to single-agent treatments.
Conclusions:
- Isoform-selective PI3K inhibition elicits unique adaptive signaling responses that can be mapped and exploited for therapeutic benefit.
- Combination strategies targeting specific PI3K isoforms are crucial for overcoming treatment resistance and enhancing efficacy in pancreatic cancer.
- Understanding and mapping these adaptive signaling networks is key to designing next-generation combinative PI3K-targeted therapies.
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