Counteracting resistance to targeted therapy in melanoma by inhibiting discoidin domain receptors

AbstractAnti-BRAF plus an anti-MEK is currently used in first line for the management of patients presenting metastatic melanomas harboring the BRAF V600E mutation. However, the main issue during targeted therapy is the acquisition of cellular resistance in 80% of the patients, which is associated with an increased metastasis due to the hyperactivation of MAP kinase pathway. Previous reports have indicated that Discoidin Domain Receptors (DDRs) 1 and 2 can activate this pathway. To study the role of DDRs in melanoma cell resistance to targeted therapy, we first determined that DDRs are overexpressed in vemurafenib resistant cells compared to sensitive cells. We demonstrated that DDRs depletion or inactivation by DDRs inhibitors such as dasatinib or CR-13542 reduces tumor cell proliferation, due to a decrease of MAP kinase pathway activity in resistant cells. Finally, we confirmed these results in vivo in a xenograft mouse model and show that DDRs could be new therapeutic targets in resistant patients with metastatic melanoma. We propose that dasatinib could be a second-line treatment after the bi-therapy in resistant patients overexpressing DDRs.

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Real World Outcomes in Patients with Advanced Melanoma Treated in Alberta, Canada: A Time-Era Based Analysis

Current Oncology ◽

10.3390/curroncol28050338 ◽

2021 ◽

Vol 28 (5) ◽

pp. 3978-3986

Author(s):

Rodrigo Rigo ◽

Jordan Doherty ◽

Kim Koczka ◽

Shiying Kong ◽

Philip Q. Ding ◽

...

Keyword(s):

Targeted Therapy ◽

Map Kinase ◽

Real World ◽

Immune Checkpoint ◽

Single Agent ◽

Advanced Melanoma ◽

First Line ◽

Term Survival ◽

Map Kinase Pathway ◽

Kinase Pathway

Immune checkpoint and MAP kinase pathway inhibitors can significantly improve long-term survival for patients with melanoma. There is limited real-world data of these regimens’ effectiveness. We retrospectively analyzed 402 patients with unresectable and metastatic melanoma between August 2013 and July 2020 treated with immune checkpoint inhibitors and MAP kinase pathway targeted therapy in Alberta, Canada. Overall survival (OS) was compared using Kaplan–Meier and Cox regression analyses. Subgroup survival outcomes were analyzed by first-line treatment regime and BRAF mutation status. Three treatment eras were defined based on drug access: prior to August 2013, August 2013 to November 2016, and November 2016 to July 2020. Across each era, there were improvements in median OS: 11.7 months, 15.9 months, and 33.6 months, respectively. Patients with BRAF mutant melanoma had improved median OS when they were treated with immunotherapy in the first line as opposed to targeted therapy (median OS not reached for immunotherapy versus 17.4 months with targeted treatment). Patients with BRAF wild-type melanomas had improved survival with ipilimumab and nivolumab versus those treated with a single-agent PD-1 inhibitor (median OS not reached and 21.2 months). Our real-world analysis confirms significant survival improvements with each subsequent introduction of novel therapies for advanced melanoma.

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Extracellular Zinc Triggers ERK-dependent Activation of Na+/H+Exchange in Colonocytes Mediated by the Zinc-sensing Receptor

Journal of Biological Chemistry ◽

10.1074/jbc.m406581200 ◽

2004 ◽

Vol 279 (50) ◽

pp. 51804-51816 ◽

Cited By ~ 73

Author(s):

Hagit Azriel-Tamir ◽

Haleli Sharir ◽

Betty Schwartz ◽

Michal Hershfinkel

Keyword(s):

Cell Proliferation ◽

Map Kinase ◽

Ph Homeostasis ◽

Ht29 Cells ◽

Intracellular Release ◽

Map Kinase Pathway ◽

Zinc Sensing ◽

Multiple Signaling ◽

Kinase Pathway

Extracellular zinc promotes cell proliferation and its deficiency leads to impairment of this process, which is particularly important in epithelial cells. We have recently characterized a zinc-sensing receptor (ZnR) linking extracellular zinc to intracellular release of calcium. In the present study, we addressed the role of extracellular zinc, acting via the ZnR, in regulating the MAP kinase pathway and Na+/H+exchange in colonocytes. We demonstrate that Ca2+release, mediated by the ZnR, induces phosphorylation of ERK1/2, which is highly metal-specific, mediated by physiological concentrations of extracellular Zn2+but not by Cd2+, Fe2+, Ni2+, or Mn2+. Desensitization of the ZnR by Zn2+, is followed by ∼90% inhibition of the Zn2+-dependent ERK1/2 phosphorylation, indicating that the ZnR is a principal link between extracellular Zn2+and ERK1/2 activation. Application of both the IP3pathway and PI 3-kinase antagonists largely inhibited Zn2+-dependent ERK1/2 phosphorylation. The physiological significance of the Zn2+-dependent activation of ERK1/2 was addressed by monitoring Na+/H+exchanger activity in HT29 cells and in native colon epithelium. Preincubation of the cells with zinc was followed by robust activation of Na+/H+exchange, which was eliminated by cariporide (0.5 μm); indicating that zinc enhances the activity of NHE1. Activation of NHE1 by zinc was totally blocked by the ERK1/2 inhibitor, U0126. Prolonged acidification, in contrast, stimulates NHE1 by a distinct pathway that is not affected by extracellular Zn2+or inhibitors of the MAP kinase pathway. Desensitization of ZnR activity eliminates the Zn2+-dependent, but not the prolonged acidification-dependent activation of NHE1, indicating that Zn2+-dependent activation of H+extrusion is specifically mediated by the ZnR. Our results support a role for extracellular zinc, acting through the ZnR, in regulating multiple signaling pathways that affect pH homeostasis in colonocytes. Furthermore activation of both, ERK and NHE1, by extracellular zinc may provide the mechanism linking zinc to enhanced cell proliferation.

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