25 Strategies to overcome phenotype switch-driven therapy resistance in melanoma

Abstract

ABSTRACT Introduction Phenotype switching is a key mechanism contributing to therapy resistance and metastasis in melanoma. It is marked by high expression of several receptor tyrosine kinases, most prominently AXL, and associated with resistance to the clinically oft-used BRAF and MEK inhibitors. Furthermore, it has recently been suggested that phenotype switching also contributes to resistance to immune checkpoint blockade in melanoma. Results and discussions We have shown previously that upregulation of AXL occurs concurrently with the downregulation of the melanocytic lineage transcription factor MITF and its downstream protein Melan-A1. Furthermore, we recently showed that most melanomas are highly heterogeneous for AXL expression, both untreated tumours and treatment-resistant ones. This observation provided the framework for a concept to differentially target these distinct AXL-high and -low populations. On the one hand, we targeted AXL-expressing melanoma cells by a novel antibody-drug conjugate, AXL-107-MMAE. On the other hand, the MITF-high, AXL-low melanoma cells were targeted with MAPK pathway inhibitors. Therefore, by eliminating distinct populations within heterogeneous melanoma cell pools, AXL-107-MMAE and MAPK pathway inhibitors cooperatively inhibited tumour growth in vitro and in vivo. Lastly, by inducing AXL transcription, BRAF/MEK inhibitors further potentiated the efficacy of AXL-107-MMAE2. Although the correlation between phenotype switching and resistance to targeted agents such as BRAF/MEK inhibitors has been well described, it is not well established how melanoma cells, especially in patients or in vivo, can acquire this state. Furthermore, it is as unclear if there is any functional interaction between the immune system and the phenotype switch. Investigating any such relationship may contribute to the development of therapies that aim to prevent the acquisition of an AXL-high, treatment-refractory state. We will present results of recent efforts to better understand the role that immune cells may play in the establishment of a phenotype switch and how we may re-sensitise tumour cells that have become resistant to T cell therapy as a consequence.