JAK1 Inhibitors May Be New Option To Treat Resistant Melanoma

Prof. Ze'ev Ronai Ph.D Scientific Director Sanford-Burnham's La JollaMedicalResearch.com Interview with:
Prof. Ze’ev Ronai Ph.D
Scientific Director
Sanford-Burnham’s La Jolla

Medical Research: What is the background for this study? What are the main findings?

Prof. Ronai: There is an urgent need to find new approaches to treat melanoma in patients that are resistant to current therapeutic regimes—and this represents a significant percent of melanoma patients.  We used  samples from patients with drug resistant tumors  to study the molecular basis of resistance and screened for genes involved in the process.

We have identified a new player in melanoma resistance to therapy—a molecular target, which provides the basis for clinical trials with drugs currently available to these targets. We found that JAK1 kinase is one target that  is upregulated in the resistant tumors. Inhibiting JAK1 kinase can effectively overcome such resistance. 

Medical Research: What should clinicians and patients take away from your report?

Prof. Ronai: There is a new option for treating patients with  melanoma resistance to vemurafenib, by targeting the JAK1 signaling pathway, possibly in combination with targeting of BRAF and EGFR.  Also, there is a way to identify the patients that would respond to such combination therapy by assessing the levels of components we have identified in this regulatory axis – including RNF125, JAK1 and EGFR.

Medical Research: What recommendations do you have for future research as a result of this study?

Prof. Ronai: The next step is to validate our findings in independent cohorts of tumors resistant to drugs commonly used in melanoma, including MEK and BRAF inhibitors, and assess whether administration of JAK1 inhibitors could serve to prevent the emergence of resistant tumors.


Downregulation of the Ubiquitin Ligase RNF125 Underlies Resistance of Melanoma Cells to BRAF Inhibitors via JAK1 Deregulation

Hyungsoo Kim,Dennie T. Frederick,Mitchell P. Levesque,Zachary A. Cooper,Yongmei Feng,Clemens Krepler,Laurence Brill,Yardena Samuels, Nicholas K. Hayward,Ally Perlina,Adriano Piris,Tongwu Zhang,Ruth Halaban,Meenhard M. Herlyn,Kevin M. Brown, Jennifer A. Wargo, Reinhard Dummer, Keith T. Flaherty, Ze’ev A. Ronai

Cell Reports: DOI: http://dx.doi.org/10.1016/j.celrep.2015.04.049

Published Online: May 28, 2015

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MedicalResearch.com Interview with: Prof. Ze’ev Ronai Ph.D, Scientific Director, & Sanford-Burnham’s La Jolla (2015). JAK1 Inhibitors May Be New Option To Treat Resistant Melanoma