Antitumor effects of the multi-target tyrosine kinase inhibitor cabozantinib: a comprehensive review of the preclinical evidence

Abstract

Introduction: Altered receptor tyrosine kinase (RTK) signaling contributes to tumorigenesis and suppression of immune-mediated destruction of cancer cells. Cabozantinib is an oral tyrosine kinase inhibitor that inhibits several RTKs involved in tumorigenesis, and is approved for the treatment of patients with progressive metastatic medullary thyroid cancer, advanced renal cell carcinoma, and hepatocellular carcinoma that has been previously treated with sorafenib. Areas covered: We present an up-to-date evaluation of preclinical evidence for RTK inhibition with cabozantinib, specifically VEGFR, MET, KIT, RET, AXL, FLT3, and associated antitumor effects. Preclinical investigations of cabozantinib in combination with other anticancer drugs are also reviewed. Expert opinion: Preclinical evidence shows that cabozantinib has antitumor activity against various cancer cells and exhibits synergy with other anticancer agents, including immune checkpoint inhibitors and hormone receptor or metabolic pathway inhibitors. Further optimization of cabozantinib treatment requires the identification of biomarkers of response and resistance, and exploration of complementary drug targets. Investigation of mechanisms of adaptive resistance, such as epithelial to mesenchymal transition (cancer intrinsic) and immunomodulation by the tumor microenvironment (cancer extrinsic), as well as identification of novel drug targets based on characterization of cancer stem cell metabolomic phenotypes, appear to be promising approaches.

Overcoming Resistance: FLT3 Inhibitors Past, Present, Future and the Challenge of Cure

“…Cabozantinib is an oral multitarget inhibitor of FLT3, AXL, MET, VEGFR, and KIT showing a potent inhibition of FLT3-ITD mut cell lines with D835 resistant mutations [ 91 ]. It is already approved for the treatment of patients with progressive metastatic medullary thyroid cancer, with hepatocellular carcinoma after Sorafenib and adults with advanced renal cell carcinoma who are treatment naïve with intermediate or poor risk, or who have received prior VEGFR targeted therapy [ 92 ]. The preclinical results in AML and clinical benefit, achieved in the treatment of other cancers, suggest a possible role of Cabozantinib in future clinical trials enrolling R/R FLT3 mut AML.…”

Cabozantinib combination therapy for the treatment of solid tumors: a systematic review

“… 2 Simultaneous inhibition of abnormal MET signaling, which is associated with cell invasion, metastasis, tumor proliferation, and angiogenesis, and AXL signaling, which is linked with increased proliferation, invasion, and metastasis, allows cabozantinib to target multiple parallel key pathways involved in tumor vascularization and growth. 3 – 5 Cabozantinib also targets other specific receptor tyrosine kinases involved in tumorigenesis, including RET, KIT, FLT3, ROS1, MER, TYRO3, TRKB, and TIE-2. 6 – 8 The efficacy of cabozantinib monotherapy has been demonstrated in several solid tumor types, including renal cell carcinoma (RCC), 9 , 10 hepatocellular carcinoma (HCC) 11 and medullary thyroid cancer 12 based on data from phase II and III randomized controlled trials (RCTs).…”

Cabozantinib-Loaded PLGA Nanoparticles: A Potential Adjuvant Strategy for Surgically Resected High-Risk Non-Metastatic Renal Cell Carcinoma

“…RCC management has advanced significantly with the advent of newer generation TKIs, such as cabozantinib (CZ), that are effective in the first-line setting for intermediate- or poor-risk metastatic RCC, with significant clinical benefits in the progression-free survival and overall response rate [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ]. CZ is an oral, potent multi-target TKI that targets the VEGF receptor (VEGFR)-2 and several other receptor tyrosine kinases (RTKs), including the hepatocyte growth factor receptor (MET), the TAM (TYRO-3, AXL, and MER) family of receptor kinases, the ROS proto-oncogene 1, the c-kit proto-oncogene product, the Fms-related receptor tyrosine kinase 3, the tropomyosin receptor kinase B, the angiopoietin-1 receptor, and the RET proto-oncogene [ 34 , 35 , 39 , 41 , 42 , 44 ]. Compared to other pure anti-angiogenic TKIs, the concomitant inhibition of multiple clinically relevant RTKs with a greater potency provided by CZ interferes with tumor progression, metastasis, angiogenesis, and therapeutic resistance to VEGF inhibition through dual multi-facet effects on the tumor cells and their microenvironment [ 34 , 35 , 39 , 41 , 42 , 44 ].…”

“…CZ is an oral, potent multi-target TKI that targets the VEGF receptor (VEGFR)-2 and several other receptor tyrosine kinases (RTKs), including the hepatocyte growth factor receptor (MET), the TAM (TYRO-3, AXL, and MER) family of receptor kinases, the ROS proto-oncogene 1, the c-kit proto-oncogene product, the Fms-related receptor tyrosine kinase 3, the tropomyosin receptor kinase B, the angiopoietin-1 receptor, and the RET proto-oncogene [ 34 , 35 , 39 , 41 , 42 , 44 ]. Compared to other pure anti-angiogenic TKIs, the concomitant inhibition of multiple clinically relevant RTKs with a greater potency provided by CZ interferes with tumor progression, metastasis, angiogenesis, and therapeutic resistance to VEGF inhibition through dual multi-facet effects on the tumor cells and their microenvironment [ 34 , 35 , 39 , 41 , 42 , 44 ]. In particular, CZ has a unique anti-tumor immunomodulatory profile because several targets of CZ, including VEGFR2, MET, and the TAM kinases, play crucial roles in mediating the immunosuppressive tumor microenvironment in metastatic RCC.…”