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Cooperative induction of receptor tyrosine kinases contributes to adaptive MAPK drug resistance in melanoma through the PI3K pathway.
- Source :
-
Cancer reports (Hoboken, N.J.) [Cancer Rep (Hoboken)] 2023 Feb; Vol. 6 (2), pp. e1736. Date of Electronic Publication: 2022 Oct 17. - Publication Year :
- 2023
-
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.<br /> (© 2022 The Authors. Cancer Reports published by Wiley Periodicals LLC.)
- Subjects :
- Humans
Vemurafenib therapeutic use
Indoles pharmacology
Indoles therapeutic use
Sulfonamides pharmacology
Sulfonamides therapeutic use
Proto-Oncogene Proteins B-raf genetics
Proto-Oncogene Proteins B-raf metabolism
Proto-Oncogene Proteins B-raf therapeutic use
Receptor Protein-Tyrosine Kinases genetics
Receptor Protein-Tyrosine Kinases metabolism
Receptor Protein-Tyrosine Kinases therapeutic use
Drug Resistance, Neoplasm genetics
Tyrosine therapeutic use
Phosphatidylinositol 3-Kinases therapeutic use
Melanoma drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 2573-8348
- Volume :
- 6
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Cancer reports (Hoboken, N.J.)
- Publication Type :
- Academic Journal
- Accession number :
- 36251678
- Full Text :
- https://doi.org/10.1002/cnr2.1736