An In Vitro Analysis of TKI-Based Sequence Therapy in Renal Cell Carcinoma Cell Lines

Abstract

The tyrosine kinase inhibitor (TKI) cabozantinib might impede the growth of the sunitinib-resistant cell lines by targeting MET and AXL overexpression in metastatic renal cell carcinoma (mRCC). We studied the role of MET and AXL in the response to cabozantinib, particularly following long-term administration with sunitinib. Two sunitinib-resistant cell lines, 786-O/S and Caki-2/S, and the matching 786-O/WT and Caki-2/WT cells were exposed to cabozantinib. The drug response was cell-line-specific. The 786-O/S cells were less growth-inhibited by cabozantinib than 786-O/WT cells (p-value = 0.02). In 786-O/S cells, the high level of phosphorylation of MET and AXL was not affected by cabozantinib. Despite cabozantinib hampering the high constitutive phosphorylation of MET, the Caki-2 cells showed low sensitivity to cabozantinib, and this was independent of sunitinib pretreatment. In both sunitinib-resistant cell lines, cabozantinib increased Src-FAK activation and impeded mTOR expression. The modulation of ERK and AKT was cell-line-specific, mirroring the heterogeneity among the patients. Overall, the MET- and AXL-driven status did not affect cell responsiveness to cabozantinib in the second-line treatment. The activation of Src-FAK might counteract cabozantinib activity and contribute to tumor survival and may be considered an early indicator of therapy response.

Molecular and functional characterization of reversible‐sunitinib‐tolerance state in human renal cell carcinoma

“…However, we have recently reported that a c‐MET and AXL‐driven status did not improve cell responsiveness to cabozantinib, and intracellular signalling for cell proliferation and survival, including Src‐FAK activation, was triggered. 49 In this study, FAK was also activated after acute and prolonged treatment with sunitinib, suggesting similar redundant strategies of the cellular response to targeted therapy with TKIs.…”

Polygenic risk score model for renal cell carcinoma in the Korean population and relationship with lifestyle-associated factors

“…Renal cell carcinoma (RCC) accounts for 90% of kidney cancers and ranks as the seventh most common cancer in the western world; it constitutes approximately 3% of all cancer diagnoses worldwide [ 1 , 2 ]. In Asia, the incidence of RCC has increased due to the adoption of western lifestyles [ 3 ].…”

Molecular Mechanisms of Tumor Progression and New Therapeutic Strategies for Urological Cancers

“…Moreover, in 786-O/S cells, cabozantinib did not significantly reduce the phosphorylation levels of MET and AXL. Interestingly, among the alternative resistance mechanisms to TKIs, the activation of the Src-FAK signaling pathway seems to counteract the effects of cabozantinib, suggesting its role as an early indicator of the therapy response [8].…”