Non-canonical ITGB2 signaling mediates resistance to TKI

Objective Lung cancer is the leading cause of cancer-related deaths worldwide. Small cell lung cancer (SCLC) is an extremely aggressive type of lung cancer. Median survival of SCLC patients is 6 – 12 months. Epidermal growth factor (EGF) signaling plays an important role in triggering SCLC. Furthermore, reports have shown that growth factor-dependent signals and alpha-, beta-integrin (ITGA, ITGB) heterodimer receptors functionally cooperate to integrate their signaling pathways. However, the precise role of non-canonical integrin signaling regulating EGF receptor (EGFR) activation in SCLC is unknown.

Results In the present work we detected high ITGB2 and ITGA2 expression levels in SCLC by meta-analysis of RNA-sequencing data deposited at The Cancer Genome Atlas and qRT-PCR-based expression analysis of retrospectively collected human lung tissue samples. In addition, we showed that ITGB6 and ITGA2 were highly expressed in non-small cell lung cancer (NSCLC). Further, high ITGB2 levels in SCLC correlated with enhanced EGF signaling. Protein extracts analysis in SCLC and NSCLC cell lines revealed that ITGB2 interacts and activates EGFR in an ITGB6-dependent manner. Moreover, ITGB2 loss-of-function sensitizes SCLC cells to Erlotinib, an EGFR-inhibitor. Interestingly, activation of the EGFR receptor by non-canonical ligand ITGB3 binding recruits KRAS to the complex, which in turn results in prominent vimentin activation. This non-canonical ITGB2-KRAS signal axis serves as a driving force for NSCLS to SCLC phenotypical transformation. Conclusion: We uncovered a mechanism of ITGB2-mediated EGFR activation in SCLC that explains EGFR-inhibitor resistance independently from EGFR mutations, suggesting a new mechanism of cellular reprograming inside lung cancer subtypes and promising therapies against SCLC targeting ITGB2.

• References

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