Ligand-Independent EPHA2 Signaling Drives the Adoption of a Targeted Therapy–Mediated Metastatic Melanoma Phenotype

Abstract

Many patients with BRAF inhibitor resistance can develop disease at new sites, suggesting that drug-induced selection pressure drives metastasis. Here we used mass spectrometry-based phosphoproteomic screening to uncover ligand-independent EphA2 signaling as an adaptation to BRAF inhibitor therapy that led to the adoption of a metastatic phenotype. The EphA2-mediated invasion was AKT-dependent and readily reversible upon removal of drug as well as through PI3K and AKT inhibition. In xenograft models, BRAF inhibition led to the development of EphA2 positive metastases. A retrospective analysis of melanoma patients on BRAF inhibitor therapy showed that 68% of those failing therapy develop metastases at new disease sites, compared to 35% in patients on dacarbazine. Further IHC staining of melanoma specimens taken from patients on BRAF inhibitor therapy as well as metastatic samples taken from patients failing therapy showed increased EphA2 staining. We suggest that inhibition of ligand-independent EphA2 signaling may limit metastases associated with BRAF inhibitor therapy.

One-Bead–Two-Compound Thioether Bridged Macrocyclic γ-AApeptide Screening Library against EphA2

“…43,44 Recent findings suggest that EphA2 overexpression is a key factor contributing to multiple cancers such as melanoma, ovarian, lung, and breast. 45–47 Therefore, EphA2 is a promising target for cancer therapeutic development. Considerable efforts have started to be made to identify inhibitors that block the capability of EphA2 for the phosphorylation of its downstream protein substrates, thereby dampening EphA2 mediated cell signaling.…”

Non-genomic and Immune Evolution of Melanoma Acquiring MAPKi Resistance

“…This point is of particular importance given the highly dynamic (i.e., out-of-range) up-expression ( c-MET, YAP1, EPHA2 (Paraiso et al, 2014)) or down-expression ( LEF1 , TAP1, B2M, CD8A, DUSP4 ) events occurring with the evolution of MAPKi-resistant in melanoma (Figure 7C). It may not be surprising to find that the expression levels of genes reflective of CD8 T-cell and antigen presentation abundance and function were linked to patient survival given the relatively high mutation/neoantigen load and immunogenicity of melanoma and the clinical efficacy of PD-1 targeting in melanoma.…”

Cancer cells exploit adaptive mitochondrial dynamics to increase tumor cell invasion

“…17 Thus, the appearance of a more invasive, potentially pro-metastatic phenotype associated with drug treatment may not necessarily predict disease progression in patients. 17 On the other hand, as elegantly illustrated in the case of B-Raf inhibitors, 19 integrating clinical data with pre-clinical observations confirmed a clear undesired pro-metastatic effect of these agents in the clinic. Therefore, before rushing these compounds to the clinic, it may be desirable to pursue retrospective analysis of patients treated with these agents, and see whether treatment failure was associated with the development new distal metastasis.…”

“…For instance, several of the DNA-targeting agents (cyclophosphamide, bleomycin, doxorubicin, cytarabine, 5-azacytidine, aphidicoline), RNA targeting drugs (actinomycin D, mithramycin), and the antifolate compound methotrexate were all associated with pro-metastatic effects. 17 Certain molecular targeted therapies seem to engender similar responses; for instance antiangiogenic agents, geldanamycinbased Hsp90 inhibitors 18 and B-Raf inhibitors 19 were shown to paradoxically increase metastatic competency. It is interesting that a common feature of such disparate molecular therapies is activation of the PI3K/Akt signaling axis.…”