Abstract
Over the last decade, the treatment of tumor patients has been revolutionized by the highly successful introduction of novel targeted therapies, in particular small-molecule kinase inhibitors and monoclonal antibodies, as well as by immunotherapies. Depending on the mutational status, BRAF and MEK inhibitor combinations or immune checkpoint inhibitors are current first-line treatments for metastatic melanoma. However, despite great improvements of survival rates limitations due to tumor heterogeneity, primary and acquired therapy resistance, immune evasion, and economical considerations will need to be overcome. Accordingly, ongoing clinical trials explore the individualized use of small-molecule drugs in new targeted therapy combinations based on patient parameters and tumor biopsies. With focus on melanoma therapy this review aims at providing a comprehensive overview of such novel alternative and combinational therapy strategies currently emerging from basic research. The molecular principles and drug classes that may hold promise for improved tumor therapy combination regimens including kinase inhibition, induction of apoptosis, DNA-damage response inhibition, epigenetic reprogramming, telomerase inhibition, redox modulation, metabolic reprogramming, proteasome inhibition, cancer stem cell transdifferentiation, immune cell signaling modulation, and others, are explained in brief. In addition, relevant targeted therapy combinations in current clinical trials and individualized treatment strategies are highlighted.
Highlights
Cancer pathogenesis evolves like a drama with a series of acts—including tumor initiation, promotion, progression, invasion, immune evasion, metastasis, chemo-resistance, and further progression ([1,2,3] and others)
The most common driver mutation occurring in over 50% of patients affects the serine/threonine protein kinase BRAF (BRAFV600E ), a downstream effector of growth factor receptor signaling, that can be therapeutically targeted by specific BRAFV600mut inhibitors (BRAFi) [10]
Different mechanisms of acquired therapy resistance to either monotherapy with BRAFi or combination treatment could be identified in melanoma [8,13,14,15]: In response to BRAFi, reactivation of the mitogen activated protein kinase (MAPK) pathway, e.g., due to switching among BRAF, ARAF and CRAF isoforms, and enhanced insulin like growth factor (IGF)-IR/PI3K signaling occurred [13]
Summary
Cancer pathogenesis evolves like a drama with a series of acts—including tumor initiation, promotion, progression, invasion, immune evasion, metastasis, chemo-resistance, and further progression ([1,2,3] and others). The most common driver mutation occurring in over 50% of patients affects the serine/threonine protein kinase BRAF (BRAFV600E ), a downstream effector of growth factor receptor signaling, that can be therapeutically targeted by specific BRAFV600mut inhibitors (BRAFi) [10]. Different mechanisms of acquired therapy resistance to either monotherapy with BRAFi or combination treatment could be identified in melanoma [8,13,14,15]: In response to BRAFi, reactivation of the mitogen activated protein kinase (MAPK) pathway, e.g., due to switching among BRAF, ARAF and CRAF isoforms, and enhanced insulin like growth factor (IGF)-IR/PI3K signaling occurred [13]. Because of parallel activation and significant signaling cross talk between these pathways, successive and combination therapies targeting different components with established small-molecule inhibitors based on an individual assessment of tumor or liquid biopsies may have the potential to overcome, or at least delay, therapy resistance (e.g., my pathway trial, NCT02091141 [7,19])
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