› Forums › General Melanoma Community › Mechanisms of BRAF Inhibitor Resistance in Metastatic Melanoma
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- February 7, 2014 at 5:04 pm
Mechanisms of BRAF Inhibitor Resistance in Metastatic Melanoma
Clin. Cancer Res 2014 Jan 24;[EPub Ahead of Print], H Rizos, AM Menzies, GM Pupo, MS Carlino, C Fung, J Hyman, LE Haydu, B Mijatov, TM Becker, SC Boyd, J Howle, S Robyn, JF Thompson, RF Kefford, RA Scolyer, GV Long
Research · February 06, 2014TAKE-HOME MESSAGE
- In an attempt to better understand resistance mechanisms in patients with BRAF V600E metastatic melanoma progressing on BRAF inhibitor therapy (vemurafenib or dabrafenib), investigators analyzed tumor samples from resected progressive or new lesions. Almost 80% of resistant tumors had restored MAPK signaling via either copy number gains or new resistance mutations while the other tumors had new or unidentified resistance pathways.
- This research provides some of the strongest evidence for the complex resistance patterns of BRAF-mutant melanoma and the difficulties in maintaining long-term disease control.
– Chris Tully, MD
ABSTRACT
Purpose
Multiple BRAF inhibitor resistance mechanisms have been described, however their relative frequency, clinical correlates, and effect on subsequent therapy have not been assessed in patients with metastatic melanoma.
Experimental Design
Fifty-nine BRAFV600 mutant melanoma metastases from patients treated with dabrafenib or vemurafenib were analyzed. The genetic profile of resistance mechanisms and tumor signaling pathway activity was correlated with clinicopathologic features and therapeutic outcomes.
Results
Resistance mechanisms were identified in 58% progressing tumors and BRAF alterations were common. Gene expression analysis revealed that MAPK activity remained inhibited in 21% of resistant tumors, and the outcomes of patients with these tumors were poor. Resistance mechanisms also occurred in pre-treatment biopsies and heterogeneity of resistance mechanisms occurred within patients and within tumors. There were no responses to subsequent targeted therapy, even when a progressing tumor had a resistance mechanism predicted to be responsive.
Conclusions
Selecting sequential drugs based on the molecular characteristics of a single progressing biopsy is unlikely to provide improved responses, and first-line therapies targeting multiple pathways will be required
Clinical Cancer ResearchBRAF Inhibitor Resistance Mechanisms in Metastatic Melanoma; Spectrum and Clinical Impact
Clin. Cancer Res 2014 Jan 24;[EPub Ahead of Print], H Rizos, AM Menzies, GM Pupo, MS Carlino, C Fung, J Hyman, LE Haydu, B Mijatov, TM Becker, SC Boyd, J Howle, S Robyn, JF Thompson, RF Kefford, RA Scolyer, GV Long
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- February 9, 2014 at 8:43 pm
Please help me understand this. Are they saying that people who progress after BRAF/MEK therapy have a lesser chance of responding to targeted therapy? I.e PD1?
thanks,
karen
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- February 9, 2014 at 10:14 pm
It is my understanding that now-a-days the term "targeted" therapy refers to chemical drugs like vemurafenib and trametinib that are deliberately designed to bind to and inhibit a "target" molecule. The BRAF and MEK inhibitors fall into this category. The term "immunotherapy" is now used to refer to general (usually naturally-occuring) immune system regulators like IL-2 and interferon. The term "check point therapy" is now used to refer to treatments (usually monocloncal antibodies) that stimulate or block very specific T-cell subpopulations like helper T cells and cytotoxic T cells. Ipi, anti-PD1 and anti-PDL1 are all check point therapies; this article is not talking about them.
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- February 9, 2014 at 10:14 pm
It is my understanding that now-a-days the term "targeted" therapy refers to chemical drugs like vemurafenib and trametinib that are deliberately designed to bind to and inhibit a "target" molecule. The BRAF and MEK inhibitors fall into this category. The term "immunotherapy" is now used to refer to general (usually naturally-occuring) immune system regulators like IL-2 and interferon. The term "check point therapy" is now used to refer to treatments (usually monocloncal antibodies) that stimulate or block very specific T-cell subpopulations like helper T cells and cytotoxic T cells. Ipi, anti-PD1 and anti-PDL1 are all check point therapies; this article is not talking about them.
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- February 9, 2014 at 10:14 pm
It is my understanding that now-a-days the term "targeted" therapy refers to chemical drugs like vemurafenib and trametinib that are deliberately designed to bind to and inhibit a "target" molecule. The BRAF and MEK inhibitors fall into this category. The term "immunotherapy" is now used to refer to general (usually naturally-occuring) immune system regulators like IL-2 and interferon. The term "check point therapy" is now used to refer to treatments (usually monocloncal antibodies) that stimulate or block very specific T-cell subpopulations like helper T cells and cytotoxic T cells. Ipi, anti-PD1 and anti-PDL1 are all check point therapies; this article is not talking about them.
Tagged: cutaneous melanoma
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