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Published on: September 8, 2021
Sequential treatment failures in response to BRAF/MEK and immune checkpoint inhibitors mediated by MAP2K2 and B2M
Craig S Richmond1, Yazhini Vallatharasu2, Jake A Deviley3
1Kabara Cancer Research Institute, Gundersen Medical Foundation, 1300 Badger Street, La Crosse, WI 54601, USA.
Abstract:
Although the treatment of metastatic melanoma has been significantly improved by both anti-BRAF/MEK and checkpoint immunotherapies, resistance to these treatment modalities remains a substantial clinical problem. Multiple clinical studies are addressing the optimal sequencing of these agents in larger patient cohorts, but successful long-term individualized treatment will likely require the elucidation of resistance mechanisms from post-progression samples. Here, we describe a patient with BRAF-V600E-positive metastatic melanoma who was sequentially treated with BRAF/MEK inhibitors (dabrafenib/trametinib) and checkpoint inhibitor immunotherapy (nivolumab, followed by pembrolizumab). After the emergence of resistance, whole exome sequencing was performed, implicating MAP2K2 and B2M mutations in loss of response to anti-BRAF/MEK and anti-PD1 therapies, respectively.
Insights
Resistance to melanoma treatments like BRAF/MEK inhibitors and immunotherapies is a challenge. Whole exome sequencing identified MAP2K2 and B2M mutations as causes of treatment resistance in a metastatic melanoma patient.
Area of Science:
- Oncology
- Genetics
- Immunology
Background:
- Metastatic melanoma treatment has advanced with BRAF/MEK inhibitors and checkpoint immunotherapies.
- However, resistance to these therapies remains a significant clinical challenge.
- Understanding resistance mechanisms is crucial for developing effective long-term, individualized treatment strategies.
Observation:
- A patient with BRAF-V600E-positive metastatic melanoma was treated sequentially with dabrafenib/trametinib and then nivolumab/pembrolizumab.
- The patient developed resistance to both treatment modalities.
- Whole exome sequencing was performed on post-progression samples.
Findings:
- Mutations in MAP2K2 were implicated in the loss of response to BRAF/MEK inhibitors.
- Mutations in B2M were associated with resistance to anti-PD1 immunotherapy.
Implications:
- These findings highlight specific genetic alterations driving resistance to distinct melanoma treatment classes.
- Elucidating these mechanisms from patient samples is vital for overcoming therapeutic resistance.
- This knowledge can guide future treatment sequencing and the development of novel therapeutic approaches for metastatic melanoma.
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