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)

The androgen receptor (AR) is a critical transcription factor in prostate cancer (PC) pathogenesis. Its activity in malignant cells is dependent on interactions with a diverse set of co-regulators. These interactions fluctuate depending on androgen availability. For example, the androgen depletion increases the dependence of castration-resistant PCs (CRPCs) on the ACK1 and HOXB13 cell survival pathways. Activated ACK1, an oncogenic tyrosine kinase, phosphorylates cytosolic and nuclear proteins, thereby avoiding the inhibitory growth consequences of androgen depletion. Notably, ACK1-mediated phosphorylation of histone H4, which leads to epigenetic upregulation of AR expression, has emerged as a critical mechanism of CRPC resistance to anti-androgens. This resistance can be targeted using the ACK1-selective small-molecule kinase inhibitor (R)- 9b. CRPCs also deploy the bromodomain and extra-terminal domain protein BRD4 to epigenetically increase HOXB13 gene expression, which in turn activates the MYC target genes AURKA/AURKB. HOXB13 also facilitates ligand-independent recruitment of the AR splice variant AR-V7 to chromatin, compensating for the loss of the chromatin remodeling protein, CHD1, and restricting expression of the mitosis control gene HSPB8. These studies highlight the crosstalk between AR-ACK1 and AR-HOXB13 pathways as key mediators of CRPC recurrence.
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PMID:ACK1-AR and AR-HOXB13 signaling axes: epigenetic regulation of lethal prostate cancers. 3288 68

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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