A novel anti-melanoma SRC-family kinase inhibitor
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Ruth Halaban1, Antonella Bacchiocchi1, Robert Straub1, Jian Cao2, Mario Sznol3, Deepak Narayan4,*, Ahmed Allam5, Michael Krauthammer2,5,6 and Tarek S. Mansour7
1 Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA
2 Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
3 Comprehensive Cancer Center Section of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut, USA
4 Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, USA
5 Department of Quantitative Biomedicine, University of Zurich, Zurich, Switzerland
6 Program in Computational Biology and Bioinformatics, Yale University School of Medicine, New Haven, Connecticut, USA
7 Sabila Biosciences LLC, New City, New York, USA
* Now deceased
|Ruth Halaban,||email:||[email protected]|
Keywords: melanoma; SRC-family kinase inhibitors; MAPK; MITF
Received: December 26, 2018 Accepted: March 04, 2019 Published: March 19, 2019
The major drawback of melanoma therapy with BRAF and MAPK inhibitors is the innate and acquired drug resistance. We therefore explored alternative targets and developed a new compound, SAB298, that is a SRC-family kinase (SFK) inhibitor. The drug is cytotoxic to patient-derived melanoma cells regardless of oncogene expression and inhibits tumor growth in vivo. As expected, it inhibited SRC and PI3K activity, and had the additional property of ERBB2 inhibition, that lead to inactivation of the two ERK phosphatases PP2A and SHP2. In 57% of the melanoma cell lines tested, the consequent increase in ERK activity lead to proteolytic degradation of its substrate, the lineage specific transcription factor MITF, likely contributing to growth arrest. Treatment with a combination of SAB298 and AZD6244 (selumetinib), induced a synergistic growth inhibition, suggesting that the new compound could be used in the clinic as a substitute for, or in combination with MAPK inhibitors.
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