Resistance to Molecularly Targeted Therapies in Melanoma

Abstract

Malignant melanoma is the most aggressive type of skin cancer with invasive growth patterns. In 2021, 106,110 patients are projected to be diagnosed with melanoma, out of which 7180 are expected to die. Traditional methods like surgery, radiation therapy, and chemotherapy are not effective in the treatment of metastatic and advanced melanoma. Recent approaches to treat melanoma have focused on biomarkers that play significant roles in cell growth, proliferation, migration, and survival. Several FDA-approved molecular targeted therapies such as tyrosine kinase inhibitors (TKIs) have been developed against genetic biomarkers whose overexpression is implicated in tumorigenesis. The use of targeted therapies as an alternative or supplement to immunotherapy has revolutionized the management of metastatic melanoma. Although this treatment strategy is more efficacious and less toxic in comparison to traditional therapies, targeted therapies are less effective after prolonged treatment due to acquired resistance caused by mutations and activation of alternative mechanisms in melanoma tumors. Recent studies focus on understanding the mechanisms of acquired resistance to these current therapies. Further research is needed for the development of better approaches to improve prognosis in melanoma patients. In this article, various melanoma biomarkers including BRAF, MEK, RAS, c-KIT, VEGFR, c-MET and PI3K are described, and their potential mechanisms for drug resistance are discussed.

Keywords: TKIs; biomarkers; melanoma; molecularly targeted therapies; resistance.

Figure 1

Predominant signaling pathways contributing to melanomagenesis and progression. Phosphorylation of receptor tyrosine kinases mesenchymal epithelial transition factor (c-MET), receptor-tyrosine kinase Kit (c-KIT) and vascular endothelial growth factor receptor (VEGFR) initiates signaling pathways resulting in proliferation, survival, motility, and angiogenesis. Activating mutations in downstream pathway components, such as reticular activating system (RAS), rapidly accelerated fibrosarcoma (RAF), and mitogen-activated protein kinase (MEK), confer constitutive pathway activation despite absence of growth signals [40,41,42]. Activation of epithelial mesenchymal transition (EMT) has been implicated in acquired resistance to multiple drugs that target aberrant signaling.

Figure 2

Activating mutations and activation of alternative upstream receptors confer resistance to inhibitors targeting aberrant MAPK signaling. Mutations in RAS, RAF, and MEK, as well as RAF amplification and activation of RAS-independent RAF variants, have been implicated in bypassing MAPK inhibition. Upregulation and activation of additional receptor tyrosine kinases may also contribute to enhanced MAPK signaling or alternative pathway activation, such as PI3K/Akt [56,57,58,59,60]. EMT has also been shown to contribute to BRAF inhibitor resistance.

Figure 3

MAPK, PI3K, and angiogenic reactivation confers resistance to c-KIT and VEGFR TKIs [1]. Activating c-KIT mutations and pathway reactivation by growth signals from the tumor microenvironment (TME) contribute to resistance to c-KIT TKIs [129,130]. Angiogenic signaling from tumor-associated macrophages as well as pathway reactivation via VEGFR co-receptor NRP-1 may contribute VEGFR TKI resistance in melanoma [136,137,138].