It has been reported that inhibition of STAT3 by sunitinib contributes to the induction of apoptosis in renal cell carcinoma. Moreover, STAT3 is known to have functional single nucleotide polymorphisms. These SNPs have been reported to be predictive tools for the efficacy of IFN treatment against metastatic renal cell carcinoma. Based on these reports and the present study, we hypothesized that STAT3 would be a critical factor for the treatment of renal cell carcinoma and toxicity to skin tissue, and that responsibility of STAT3 depend on functional SNPs. However, it remains unclear that the everolimus induced cell growth inhib ition in Caki 1 and HepG2 cells was unaffected by stattic treatment. SNPs genotyping analysis of STAT3 in vari ous cells is required to address these issues in the future.

In addition, through our research, patients carrying a high risk of dermatological toxicity by molecular target drugs could be identified by testing for STAT3 polymor phisms. And, ultraviolet irradiation increases the potential of dermatological side effects induced by mo lecular target drugs in clinical reports. STAT3 rep resents a critical regulator of keratinocytes kinase inhibitor FR 180204 in response to UVB irradiation. After UVB irradiation, STAT3 is rapidly downregulated in keratinocytes, which leads to decreased cell cycle progression and increased sensitivity to UVB induced apoptosis. It has also been reported that UV specifically decreases the DNA binding activity of STAT3. Furthermore, UV triggers the activation of members of the MAPK family, including Erk1 2, JNK, and p38 MAPK.

UV irradiation can enhance MAPK activ ity and lead to a greater phosphorylation of STAT3 at Ser727 in the presence of everolimus. These re sults suggest that the dermatological side effects induced by molecular target drugs can be increased potentially by UV irradiation, with repression of STAT3 activity mediat ing {from this source|order Micafungin Sodium greater phosphorylation of Ser727. However, add itional studies are necessary to clarify this potency. Conclusions In conclusion, STAT3 activation may be a key factor in everolimus induced keratinocyte cytotoxicity. More over, p38 MAPK and Erk mediated between mTOR signaling and STAT3 signaling may also play an im portant role of everolimus induced dermatological side effects.

Skin reactions caused by everolimus or other molecular target drugs may cause significant physical discomfort, thus decreasing the quality of life of pa tients or leading to the discontinuation of drug ther apy. Therefore, a mechanism based approach, and not just clinical experience based treatment strategies, to assess dermatological toxicity should be proposed to overcome this uncomfortable reaction. We advocate that cutaneous localized treatment aimed at the main tenance of the homeostasis of STAT3 activity may be an effective strategy.