Comparative analysis of MAPK and PI3K/AKT pathway activation and inhibition in human and canine melanoma

Abstract

The lack of advanced animal models of human cancers is considered a barrier to developing effective therapeutics. Canine and human melanomas are histologically disparate but show similar disease progression and response to therapies. The purpose of these studies was to compare human and canine melanoma tumours and cell lines regarding MAPK and PI3K/AKT signalling dysregulation, and response to select molecularly targeted agents. Pathway activation was investigated via microarray and mutational analysis. Growth inhibition and cell cycle effects were assessed for pathway inhibitors AZD6244 (MAPK) and rapamycin (PI3K/AKT) in human and canine melanoma cells. Human and canine melanoma share similar differential gene expression patterns within the MAPK and PI3K/AKT pathways. Constitutive pathway activation and similar sensitivity to AZD6244 and rapamycin was observed in human and canine cells. These results show that human and canine melanoma share activation and sensitivity to inhibition of cancer-related signalling pathways despite differences in activating mutations.

Homologous Mutation to Human BRAF V600E Is Common in Naturally Occurring Canine Bladder Cancer—Evidence for a Relevant Model System and Urine-Based Diagnostic Test

“…Prior to this study, canine melanomas, but no other malignancies, have been assessed for activating BRAF mutations. In two studies covering a total of 29 canine melanoma cases, none harbored an activating BRAF(V600E) mutation (42,43). By comparison, we found that the homologous canine BRAF(V595E) mutation is present in approximately 85% of canine InvTCC tumors tested, making the mutation more common in canine InvTCC than in any single type of human cancer except hairy cell leukemia (reviewed in (44)).…”

Comparative cytogenetic characterization of primary canine melanocytic lesions using array CGH and fluorescence in situ hybridization

“…Both C - MYC and C - KIT showed copy number gain in canine oral melanomas (80 and 65 % of cases, respectively), further supporting the involvement of the MAP-kinase signaling pathway in the development of canine oral melanomas. Previous studies have shown the activation of the MAP-K signaling cascade, but were unable to fully elucidate the mechanism (Angstadt et al 2012; Fowles et al 2013). Copy number gain, and subsequent overexpression, of TRPM7 and loss of SPRED1 may represent such a mechanism.…”

Defining the Value of a Comparative Approach to Cancer Drug Development

“…For example, recent work in canine melanoma demonstrates that although canine tumors possess rare mutations in BRAF and NRAS, they exhibit similar differential gene expression changes to human melanoma within downstream MAPK and PI3K/AKT pathways. (25) Thus, although the driving mutations between human and canine melanoma may differ, similar activation and sensitivity to inhibition of such shared signaling pathways underscores the translational value of studying comparative melanoma biology. This aspect of comparative oncology will continue to develop and could support initiation of so-called ‘basket’ trials wherein response of tumors with shared, credentialed biology to a specific targeted therapy are assessed, agnostic of histologic diagnosis.…”