Cooperative induction of receptor tyrosine kinases contributes to adaptive MAPK drug resistance in melanoma through the PI3K pathway

Abstract

Vemurafenib-induced drug resistance in melanoma has been linked to receptor tyrosine kinase (RTK) upregulation. The MITF and SOX10 genes play roles as master regulators of melanocyte and melanoma development. Here, we aimed to explore the complex mechanisms behind the MITF/SOX10-controlled RTK-induced drug resistance in melanoma. To achieve this, we used a number of molecular techniques, including melanoma patient data from TCGA, vemurafenib-resistant melanoma cell lines, and knock-down studies. The melanoma cell lines were classified as proliferative or invasive based upon their MITF/AXL expression activity. We measured the change of expression activity for MITF/SOX10 and their receptor (AXL/ERBB3) and ligand (NRG1/GAS6) targets known to be involved in RTK-induced drug resistance after vemurafenib treatment. We find that melanoma cell lines characterized as proliferative (high MITF low AXL), transform into an invasive (low MITF, high AXL) cell state after vemurafenib resistance, indicating novel feedback loops and advanced compensatory regulation mechanisms between the master regulators, receptors, and ligands involved in vemurafenib-induced resistance. Together, our data disclose fine-tuned mechanisms involved in RTK-facilitated vemurafenib resistance that will be challenging to overcome by using single drug targeting strategies against melanoma.

Antibody dependent cellular cytotoxicity-inducing anti-EGFR antibodies as effective therapeutic option for cutaneous melanoma resistant to BRAF inhibitors

“…Our observations are likely not limited to EGFR but could prove valid also for other RTKs that are de novo expressed on VR cells. Among these, AXL is particularly appealing since it is included in the RTK signatures of BRAFi resistant CM (Figure 1A), and it has been proposed to play a potentially important role in acquiring resistance to BRAFi and in increasing the invasive potential of CM cells (24,33,(76)(77)(78). Noteworthy, a recent single cell sequencing study revealed that a population resistant to targeted-therapy labeled as "invasive" and expressing high levels of AXL became frequently expanded in CM patient derived xenografts progressing on combined BRAF/MEK/RXR inhibition (18).…”

Dormancy of cutaneous melanoma

“…Whereas cells expressing low levels of MITF have a slow-cycling, mesenchymal-like, pro-invasive phenotype, higher levels of MITF correlate with proliferation and differentiation [ 69 – 72 ]. Interestingly, low MITF levels are also found in drug resistant melanoma cell lines, which was previously defined as hallmark of dormancy [ 73 ]. MITF acts as a “rheostat” and is considered as one of the key regulators of melanoma phenotype switching [ 71 , 74 ].…”