VEGFR Pathway & INLYTA (axitinib) MOA

VEGFR Pathway & INLYTA® (axitinib) MOA
VEGFR pathway
THE VEGFR PATHWAY IS A PRIMARY DRIVER IN RCC1,2
  • VEGF plays an important role in RCC, in which it is constitutively upregulated1,2
  • VEGF acts on 3 receptors: VEGFR-1, -2, and -3, which are implicated in pathologic angiogenesis, lymphangiogenesis, tumor growth, and cancer progression3-6
  • Preclinical evidence demonstrates that the VEGFR pathway plays a key role in continued RCC tumor growth and spread3,7
  • Preclinical activity does not necessarily correlate with clinical outcomes
INLYTA mechanism of action (MOA)
INLYTA WAS DESIGNED TO INHIBIT RECEPTOR TYROSINE KINASES, INCLUDING VEGFR-1, -2, AND -3
  • INLYTA has been shown to inhibit receptor tyrosine kinases, including VEGFR-1, -2, and -3, in vitro and in preclinical models
  • Preclinical models suggest that the VEGFR pathway contributes to tumor growth and cancer progression by stimulating pathological angiogenesis and impacting immune cell activity in the tumor microenvironment8
  • Preclinical activity does not necessarily correlate with clinical outcomes
References
  1. Brieger J, Weidt EJ, Schirmacher P, Störkel S, Huber C, Decker HJ. Inverse regulation of vascular endothelial growth factor and VHL tumor suppressor gene in sporadic renal cell carcinomas is correlated with vascular growth: an in vivo study on 29 tumors. J Mol Med (Berl). 1999;77(6):505-510.
  2. Linehan WM, Vasselli J, Srinivasan R, et al. Genetic basis of cancer of the kidney: disease-specific approaches to therapy. Clin Cancer Res. 2004;10(18, pt 2):6282S-6289S.
  3. Hu-Lowe DD, Zou HY, Grazzini ML, et al. Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res. 2008;14(22):7272-7283.
  4. Alitalo A, Detmar M. Interaction of tumor cells and lymphatic vessels in cancer progression. Oncogene. 2012;31(42):4499-4508.
  5. Koch S, Claesson-Welsh L. Signal transduction by vascular endothelial growth factor receptors. Cold Spring Harb Perspect Med. 2012;2(7):a006502.
  6. Duignan IJ, Corcoran E, Pennello A, et al. Pleiotropic stromal effects of vascular endothelial growth factor receptor 2 antibody therapy in renal cell carcinoma models. Neoplasia. 2011;13(1):49-59.
  7. Han KS, Raven PA, Frees S, et al. Cellular adaptation to VEGF-targeted antiangiogenic therapy induces evasive resistance by overproduction of alternative endothelial cell growth factors in renal cell carcinoma. Neoplasia. 2015;17(11):805-816.
  8. Yuan H, Cai P, Li Q, et al. Axitinib augments antitumor activity in renal cell carcinoma via STAT3-dependent reversal of myeloid-derived suppressor cell accumulation. Biomed Pharmacother. 2014;68(6):751-756.