Beyond the Abstract - New insights into molecular mechanisms of sunitinib-associated side effects, by Luis Antón-Aparicio and Luis Leon Mateos

BERKELEY, CA (UroToday.com) - Renal cell carcinoma is the most common cancer of the kidney. Up to 30% of patients with renal cell carcinoma present with metastatic disease, and recurrence occurs in nearly 40% of patients treated for a localized tumor.[1] New drugs are now well established for the treatment of patients with metastasic renal cell carcinoma. The use of these agents has improved overall survival to more than 2 years with sunitinib.[2]

bta renalSunitinib is a multitargeted oral tyrosine kinase inhibitor; it targets vascular endothelial growth factor receptor (VEGFR) 2, platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGF), FLT-3, and c-KIT. VEGFR and PDFGR play a key role in the pathogenesis of clear-cell carcinoma through involvement of the von Hippel–Lindau (VHL) gene, which is inactivated in up to 80% of sporadic cases of clear-cell carcinoma. The encoded protein by VHL participates in the regulation of VEGF and PDGF, that causes overexpression of these agonists of VEGFR and PDGFR. The resulting persistent stimulation may promote tumor angiogenesis, tumor growth, and metastasis.[3] Sunitinib is approved by the FDA for the treatment of patients with advanced renal cell carcinoma (favourable or intermediate risk) and in patients with imatinib-resistant gastrointestinal stromal tumors.

Although sunitinib therapy is associated with several well-characterized side effects, the molecular mechanisms underlying these toxicities remain unclear, but they be related to the effect of sunitinib in normal cells that also express sunitinib targets, or to the cross-talks between different signaling pathways.

Molecular basis of fatigue and weakness

Both the AMPK and LKB1 kinases are potential targets for sunitinib, which may impair the signaling pathway responsible for maintaining the correct energy cellular balance, resulting in fatigue and weakness (asthenia).[4] Besides, sunitinib-mediated inhibition of VEGFR may trigger:

  1. inhibition of nitric oxide synthase (NOS), resulting in a reduction in glucose uptake, and
  2. inhibition of protein kinase C (PKC), that could impair insulin-dependent glucose uptake in the muscle.[5]

 Molecular basis of hair depigmentation

Although the mechanisms causing depigmentation in response to sunitinib treatment are not fully understood, it is suggested that the inhibitory effect of sunitinib takes place at the level of melanocyte function, rather than affecting development or survival. Through the inhibition of KIT, sunitinib may prevent activation of the transcriptional regulator microphthalmia-associated transcription factor (MITF), resulting in a lack of enzymes responsible for melanin biosynthesis and, ultimately, impairing hair depigmentation.

References:

  1. Motzer RJ, Bander NH, Nanus DM. Renal-Cell carcinoma. N Engl J Med. 1996; 335 :865-875.
  2. Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009; 27: 3584-3590.
  3. Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med. 2003; 349:427-434.
  4. Fabian MA, Biggs WH 3rd, treiber DK, Atteridge CE, Azimioara MD, Benedetti Mg, et al. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol 2005;23:329–36.
  5. Richter EA, Derave W, Wojtaszewski JF. Glucose, exercise and insulin: emerging concepts. J Physiol2001;535:313–22.

 


 

Written by:
Luis Antón-Aparicio and Luis Leon Mateos (on behalf of the Galician Genitourinary Group) as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

 


 

 

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