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PI3Kβ inhibition enhances ALK-inhibitor sensitivity in ALK-rearranged lung cancer
Sarang S Talwelkar1,2, Mikko I Mäyränpää3, Julia Schüler4
1Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Finland.
Abstract:
Treatment with anaplastic lymphoma kinase (ALK) inhibitors significantly improves outcome for non-small-cell lung cancer (NSCLC) patients with ALK-rearranged tumors. However, clinical resistance typically develops over time and, in the majority of cases, resistance mechanisms are ALK-independent. We generated tumor cell cultures from multiple regions of an ALK-rearranged clinical tumor specimen and deployed functional drug screens to identify modulators of ALK-inhibitor response. This identified a role for PI3Kβ and EGFR inhibition in sensitizing the response regulating resistance to ALK inhibition. Inhibition of ALK elicited activation of EGFR, and subsequent MAPK and PI3K-AKT pathway reactivation. Sensitivity to ALK targeting was enhanced by inhibition or knockdown of PI3Kβ. In ALK-rearranged primary cultures, the combined inhibition of ALK and PI3Kβ prevented the EGFR-mediated ALK-inhibitor resistance, and selectively targeted the cancer cells. The combinatorial effect was seen also in the background of TP53 mutations and in epithelial-to-mesenchymal transformed cells. In conclusion, combinatorial ALK- and PI3Kβ-inhibitor treatment carries promise as a treatment for ALK-rearranged NSCLC.
Insights
Combining anaplastic lymphoma kinase (ALK) and PI3Kβ inhibitors shows promise for treating non-small-cell lung cancer (NSCLC). This approach overcomes resistance to ALK inhibitors by targeting key resistance pathways.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Anaplastic lymphoma kinase (ALK) inhibitors improve outcomes for ALK-rearranged non-small-cell lung cancer (NSCLC).
- Clinical resistance to ALK inhibitors is common and often involves ALK-independent mechanisms.
- Understanding resistance mechanisms is crucial for developing more effective NSCLC treatments.
Purpose of the Study:
- To identify modulators of ALK inhibitor response in ALK-rearranged NSCLC.
- To investigate the role of PI3Kβ and EGFR in ALK inhibitor resistance.
- To evaluate the efficacy of combined ALK and PI3Kβ inhibition.
Main Methods:
- Generation of tumor cell cultures from multiple regions of an ALK-rearranged clinical NSCLC specimen.
- Functional drug screens to identify resistance modulators.
- Inhibition and knockdown of PI3Kβ and EGFR pathways.
Main Results:
- ALK inhibition led to EGFR activation and reactivation of MAPK and PI3K-AKT pathways.
- PI3Kβ inhibition sensitized cancer cells to ALK inhibitors and prevented EGFR-mediated resistance.
- Combined ALK and PI3Kβ inhibition demonstrated selective targeting of cancer cells, including those with TP53 mutations and epithelial-to-mesenchymal transition.
Conclusions:
- Combined inhibition of ALK and PI3Kβ is a promising strategy to overcome ALK inhibitor resistance in NSCLC.
- This combinatorial approach effectively targets cancer cells, even in challenging genetic backgrounds.
- Further clinical investigation of ALK and PI3Kβ inhibitor combinations is warranted for ALK-rearranged NSCLC.
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