Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Targeted BRAF(V600E) suppression by selective BRAF inhibitors (BRAFi's, e.g. vemurafenib and dabrafenib) has led to a sea change in the treatment of metastatic melanoma (Long et al. 2014). Despite frequent upfront responses, acquired resistance has compromised long-term applicability (Sosman et al. 2012). Among the various mechanisms of resistance, activation of multiple receptor tyrosine kinases (RTKs) is a known critical factor that contributes to vemurafenib resistance (Luebker and Koepsell 2019), EGFR activation has been recurrently identified in a set of vemurafenib-resistant melanomas (Corcoran et al. 2012; Ji et al. 2015; Webster et al. 2014), but little is known about how EGFR, or possibly other RTKs, becomes activated. Here we report that ACK1, a protein kinase that modulates EGFR turnover, is downregulated in vemurafenib-resistant melanoma cells. We also found that ACK1 depletion with shRNA decreased EGFR degradation when activated by EGF, increased EGFR protein expression, and conferred resistance to BRAFi's both in vitro and in vivo. Vemurafenib resistance mediated by ACK1 inhibition can be reversed by EGFR inhibitor gefitinib. Our data indicate that ACK1 loss may be a post-transcriptional mechanism that increases EGFR signaling and contributes to drug resistance.
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PMID:Loss of ACK1 Upregulates EGFR and Mediates Resistance to BRAF inhibition. 3315 68


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