Abstract
Most B-Raf proto-oncogene (BRAF)-mutant melanoma tumors respond initially to BRAF inhibitor (BRAFi)/mitogen-activated protein kinase kinase 1 inhibitor (MEKi) therapy, although few patients have durable long-term responses to these agents. The goal of this study was to use an unbiased computational approach to identify inhibitors that reverse an experimentally derived BRAFi resistance gene expression signature. Using this approach, we found that ibrutinib effectively reverses this signature, and we demonstrate experimentally that ibrutinib resensitizes a subset of BRAFi-resistant melanoma cells to vemurafenib. Ibrutinib is used clinically as an inhibitor of the Src family kinase Bruton tyrosine kinase (BTK); however, neither BTK deletion nor treatment with acalabrutinib, another BTK inhibitor with reduced off-target activity, resensitized cells to vemurafenib. These data suggest that ibrutinib acts through a BTK-independent mechanism in vemurafenib resensitization. To better understand this mechanism, we analyzed the transcriptional profile of ibrutinib-treated BRAFi-resistant melanoma cells and found that the transcriptional profile of ibrutinib was highly similar to that of multiple Src proto-oncogene kinase inhibitors. Since ibrutinib, but not acalabrutinib, has appreciable off-target activity against multiple Src family kinases, it suggests that ibrutinib may be acting through this mechanism. Furthermore, genes that are differentially expressed in ibrutinib-treated cells are enriched in Yes1-associated transcriptional regulator (YAP1) target genes, and we showed that ibrutinib, but not acalabrutinib, reduces YAP1 activity in BRAFi-resistant melanoma cells. Taken together, these data suggest that ibrutinib, or other Src family kinase inhibitors, may be useful for treating some BRAFi/MEKi-refractory melanoma tumors. SIGNIFICANCE STATEMENT: MAPK-targeted therapies provide dramatic initial responses, but resistance develops rapidly; a subset of these tumors may be rendered sensitive again by treatment with an approved Src family kinase inhibitor-ibrutinub-potentially providing improved clinical outcomes.
Highlights
90% of melanoma tumors harbor activating mutations in the mitogen activated protein kinase (MAPK) pathway and most of these tumors have BRAFV600 mutations (Hodis, Watson et al 2012)
Signature creation, Summarized Reverse Gene Expression Score (sRGES) computation, and in silico validation were streamlined in the Open Cancer TherApeutic Discovery (OCTAD) pipeline which was described in the Materials and Methods section
In this study we used an unbiased computational approach to identify compounds that reverse a gene expression signature associated with melanoma BRAF inhibitors (BRAFi) resistance
Summary
90% of melanoma tumors harbor activating mutations in the MAPK pathway and most of these tumors have BRAFV600 mutations (Hodis, Watson et al 2012). We sought to identify compounds which reverse a BRAFi resistance gene signature. This systems-based approach has been widely explored in cancer drug discovery (Lamb, Crawford et al 2006, Jahchan, Dudley et al 2013, Chen, Ma et al 2017, Chen, Wei et al 2017, Subramanian, Narayan et al 2017), yet few studies have investigated resistance in melanoma. The goal is to identify drugs which could be combined with BRAFi/MEKi therapy to prevent or reverse drug resistance
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