Integrin beta-3-KRAS signaling axis (ITGB3-KRAS axis)

The Integrin beta-3-KRAS signaling axis is a critical molecular pathway involving the interaction between the integrin alpha-v beta-3 (CD51/CD61) and the KRAS GTPase, which plays a pivotal role in tumor progression and resistance to therapy (Seguin et al., 2014, Nature Cell Biology). In many epithelial cancers, particularly those with KRAS mutations or those that have developed resistance to EGFR inhibitors, the expression of alpha-v beta-3 is induced to facilitate the recruitment of KRAS to the plasma membrane (Singh et al., 2019, Cancer Research). This recruitment triggers a signaling cascade involving RalB and TBK1, which promotes a "stem-like" state and anchorage-independent survival, allowing tumor cells to evade apoptosis and survive in the absence of traditional growth factor signaling (Cheresh et al., 2014). Targeting this axis is a promising therapeutic strategy, either through the use of integrin alpha-v beta-3 antagonists like Cilengitide or through direct KRAS inhibitors like Sotorasib, to overcome drug resistance and inhibit metastasis (UniProt P05106; P01116). However, therapeutic intervention must account for the role of beta-3 integrins in platelet function to avoid bleeding risks and manage the systemic toxicities associated with KRAS inhibition (NIH, 2023).

Other names

alpha-v beta-3-KRAS pathwayITGB3-KRAS signalingavb3-KRAS axisIntegrin beta-3-KRAS complex

Inhibition of the alpha-v beta-3 integrin to disrupt its physical and functional interaction with KRAS, thereby preventing downstream survival signaling, or direct covalent inhibition of mutant KRAS proteins to block oncogenic activity.