Lung cancer is the deadliest cancer worldwide, with 1.8 million deaths in 2020, representing 18% of cancer-related deaths. The most common type of lung cancer, known as non-small cell lung carcinoma (NSCLC), often presents mutations in the EGFR gene, which can be treated with tyrosine kinase inhibitors (TKI). Unfortunately, systematic resistance to these TKIs is observed after 9 to 12 months of treatment. Several mechanisms may drive this resistance in cancers, including epithelial-to-mesenchymal transition (EMT). During EMT, cells acquire new characteristics that promote treatment resistance in the context of cancer. However, the signals and effectors orchestrating EMT in NSCLC are still poorly understood. Recent research from the laboratory has shown that the expression of the PRNP gene (coding for the cellular prion protein PrPC) is associated with the expression of EMT markers in the mesenchymal subtype of colon cancers. PrPC, whose pathological form PrPscrapie is known for its involvement in neurodegenerative diseases, has also emerged in recent years as playing a role in the occurrence of EMT in several cell types. Despite these advances, the interactions between PrPC, EMT, and TKI resistance remain poorly understood in lung cancers, which is why the research team undertook this study.
By working on several public patient and cell databases, on cell lines, and on plasma samples from patients with EGFR-mutated NSCLC, the authors were able to highlight several interesting results:
- PrPC expression correlates with EMT in NSCLC
- PrPC controls EMT in cell lines
- Reciprocal and functional interactions exist between PrPC and EGFR in NSCLC
- Blockade of PrPC expression in NSCLC cell lines increases their sensitivity to TKI
- Patients with EGFR-mutated NSCLC express more PrPC compared to patients without EGFR alterations
This study suggests a potential role of PrPC in TKI resistance in EGFR-mutated NSCLC, which needs to be validated on a larger scale. The research team has established proof of concept for the therapeutic targeting of PrPC in vivo. In this context, it will be interesting to verify whether its inhibition restores sensitivity to TKI. Finally, plasma PrPC could be useful as a marker of progression in patients with EGFR-mutated NSCLC; this possibility will need to be further evaluated.