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A functional landscape of resistance to ALK inhibition in lung cancer
Frederick H Wilson1, Cory M Johannessen2, Federica Piccioni2
1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Abstract:
We conducted a large-scale functional genetic study to characterize mechanisms of resistance to ALK inhibition in ALK-dependent lung cancer cells. We identify members of known resistance pathways and additional putative resistance drivers. Among the latter were members of the P2Y purinergic receptor family of G-protein-coupled receptors (P2Y1, P2Y2, and P2Y6). P2Y receptors mediated resistance in part through a protein-kinase-C (PKC)-dependent mechanism. Moreover, PKC activation alone was sufficient to confer resistance to ALK inhibitors, whereas combined ALK and PKC inhibition restored sensitivity. We observed enrichment of gene signatures associated with several resistance drivers (including P2Y receptors) in crizotinib-resistant ALK-rearranged lung tumors compared to treatment-naive controls, supporting a role for these identified mechanisms in clinical ALK inhibitor resistance.
Insights
Researchers identified P2Y purinergic receptors and protein kinase C (PKC) as key drivers of resistance to anaplastic lymphoma kinase (ALK) inhibitors in lung cancer. Combining ALK and PKC inhibition restored drug sensitivity, offering new therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Anaplastic lymphoma kinase (ALK) inhibitors are crucial for treating ALK-rearranged non-small cell lung cancer.
- Mechanisms of resistance to ALK inhibitors limit long-term patient benefit.
- Identifying novel resistance pathways is essential for improving therapeutic strategies.
Purpose of the Study:
- To characterize functional genetic mechanisms of resistance to ALK inhibition in ALK-dependent lung cancer cells.
- To identify novel drug resistance drivers beyond known pathways.
Main Methods:
- Large-scale functional genetic screening of ALK-dependent lung cancer cells.
- Analysis of gene expression in crizotinib-resistant versus treatment-naive ALK-rearranged lung tumors.
- Pharmacological inhibition of ALK and protein kinase C (PKC) pathways.
Main Results:
- Members of the P2Y purinergic receptor family (P2Y1, P2Y2, P2Y6) were identified as novel resistance drivers.
- P2Y receptor-mediated resistance involves a protein kinase C (PKC)-dependent mechanism.
- PKC activation alone conferred resistance to ALK inhibitors; combined inhibition restored sensitivity.
- Gene signatures of resistance drivers, including P2Y receptors, were enriched in resistant clinical tumors.
Conclusions:
- P2Y purinergic receptors and PKC activation represent significant mechanisms of ALK inhibitor resistance in lung cancer.
- Targeting both ALK and PKC pathways may overcome acquired resistance.
- These findings support the clinical relevance of identified resistance mechanisms in ALK-rearranged lung tumors.
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