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New Research Aims to Solve Resistance Problems in Melanoma Therapies


New strategies are currently being investigated to find out how to avoid resistance to immune checkpoint inhibitors and BRAF/MEK inhibitors.

Novel therapies for metastatic melanoma have given promising new options to patients, but the therapies do not work universally, and scientists do not fully understand why.

In new research published in Hematology/Oncology Clinics of North America, investigators from Vanderbilt University Medical Center and Duke University Medical Center analyzed the latest data involving resistance to immune checkpoint inhibitors (ICIs) and BRAF and MEK (BRAF/MEK) inhibitors.

They noted that both ICIs and targeted therapies have led to better overall survival (OS) in patients with advanced melanomas, something that had not been observed with chemotherapy. Yet, they said patients treated with BRAF/MEK inhibitors typically see resistance and disease progression. ICIs can provide longer-term improvement, they wrote, but the effects are heterogenous, with some patients appearing to be innately resistant to the therapy.

The authors began with a discussion of checkpoint inhibitors. ICIs are often associated with intrinsic resistance and primary progressive disease, due to lack of immune recognition, T-cell exclusion, or other causes of T-cell exhaustion, they wrote.

In addition, a number of strategies have been suggested to augment cytotoxic T-cell and tumor infiltration to improve ICI response.

“Radiation therapy broadens the spectrum of T-cell receptors among tumor-infiltrating lymphocytes, which may help to overcome innate or acquired mechanisms of resistance involving T-cell exclusion,” they wrote. “Melanoma vaccines may also augment the effect of checkpoint inhibition, particularly when directed toward particular neoantigens associated with a robust response to ICIs.”

Such vaccine-based approaches are currently under investigation, they noted.

In addition, the investigators noted that several oncolytic viruses “capitalize on defective interferon signaling to enter and replicate within cells and may therefore be used to target IFN‐γ–deficient clones and overcome associated resistance.”

They said engaging toll-like receptors within the tumor microenvironment has also been linked with innate immune activation and proinflammatory cytokine production that can potentially boost response to ICIs. Early trials have produced encouraging results in anti–PD-1/PD-L1 refractory patients treated with an intratumoral TLR9 agonist and in patients with either acquired or intrinsic resistance treated with ipilimumab (Yervoy), they added.

Turning to BRAF/MEK inhibitors, the investigators noted that mutations in BRAF occur in almost half of all melanomas. BRAF inhibitors can improve overall response rates, progression-free survival, and OS. Yet, although primary resistance to BRAF inhibitors is rare, acquired resistance is a frequent problem.

After discussing potential reasons for BRAF/MEK inhibitor resistance, the investigators outlined possible avenues to overcome such resistance. They noted that persistent MAPK signaling has been identified as playing a key role in BRAF/MEK inhibitor resistance, which raises the question of whether inhibition further downstream might mitigate MAPK reactivation.

“Mitogen-activated extracellular signal regulated kinase (ERK) is the final effector in the MAPK cascade and acts within the nucleus to promote proliferation, growth, and survival,” they said. “Preclinical studies have suggested that ERK inhibitors can independently induce regression in BRAF-mutant melanoma and may also reverse resistance to BRAF/MEK [inhibitors].”

Johnson and colleagues said early clinical trials have shown meaningful results in BRAF/MEK inhibitor–resistant patients and in treatment-naive patients with BRAF- and NRAS-mutant melanomas.

Another strategy highlighted in the study is reintroducing BRAF/MEK inhibitor therapy after at least 6 weeks off therapy in patients who previously progressed on such therapies.

“Evidence suggests that some BRAF/MEK [inhibitor]–resistant melanomas may become ‘inhibitor addicted’ and regress with short-term drug withdrawal,” the investigators wrote. “Intermittent dosing strategies may improve outcomes in these patients and are being evaluated in early phase trials.”

After outlining other potential strategies, the investigators concluded by stating there likely will not be an easy, one-size-fits-all approach to overcoming ICI and BRAF/MEK inhibitor resistance.

“Mechanisms of resistance are diverse and will require innovative and perhaps personalized management strategies,” they concluded.


Haugh AM, Salama AKS, Johnson DB. Advanced melanoma: resistance mechanisms to current therapies. Hematol Oncol Clin North Am. 2021;35(1):111-128. doi:10.1016/j.hoc.2020.09.005

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