Purpose: Medullary Thyroid Cancer (MTC) is a rare malignancy with limited treatment options in advanced stages. Tyrosine kinase inhibitors (TKIs) such as Cabozantinib (Cabo) and Selpercatinib (Loxo) have improved survival rates, yet resistance—especially non-genetic resistance—remains a major challenge. This study aimed to develop and characterise non-genetic TKI-resistant MTC cell models, identify resistance mechanisms, and explore the therapeutic potential of integrin inhibitors in overcoming resistance. Methodology: Resistant TT cell lines were developed by treating TKI-sensitive cells with escalating doses of Cabo or Loxo over eight months. TKI resistance was confirmed using cell-based assays, and whole-genome sequencing ruled out resistance-causing mutations. Transcriptomic profiling identified activated pathways through mRNA sequencing followed by Ingenuity Pathway Analysis. The ability of the integrin inhibitor Cilengitide to restore TKI sensitivity was evaluated in cell-based assays. Phosphoproteomics will further assess the molecular effects of integrin inhibition. Results: TKI-resistant cell lines exhibited significantly reduced sensitivity to TKIs without acquiring mutations linked to resistance. Transcriptomic analysis identified integrin signalling among the most activated pathways. Combination treatments with Cilengitide restored TKI sensitivity, reducing proliferation and migration in resistant cells. Conclusion: Preliminary findings suggest that integrin signalling is implicated as a driver of non-genetic TKI resistance in MTC. Targeting integrins with inhibitors such as Cilengitide shows promise in restoring TKI efficacy, offering a potential strategy to overcome resistance.