Lessons from clinical trials on triple combination of immune checkpoint inhibitors and BRAF/MEK inhibitors in BRAF-mutant melanoma

Maeda, Takahiro; Yanagi, Teruki; Ujiie, Hideyuki

doi:10.21037/atm-23-1215

“…However, in contrast, the spartalizumab combination with D/T showed survival benefit potential for BRAF-mutant colorectal cancer patients, and a single-cell RNA sequencing analysis of this cohort revealed that more effective induction of tumor cell-intrinsic immune programs and MEK/ERK inhibition is associated with better clinical outcomes [121]. As such, post-hoc analyses of different trials are required to identify tumor type-specific biomarkers for the precise selection of patients for the triple drug combination, as recently proposed [122]. For example, dual BRAF/MEK inhibition induces cleavage of pyroptosis marker gasdermin E (GSDME) and intra-tumoral T cell infiltration, but BRAFi/MEKi resistance attenuates these responses in melanoma [48].…”

Section: Co-evolution Of Intra-tumoral Immunitymentioning

confidence: 88%

Tumor Cell Resistance to the Inhibition of BRAF and MEK1/2

Chen,

Park

2023

IJMS

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BRAF is one of the most frequently mutated oncogenes, with an overall frequency of about 50%. Targeting BRAF and its effector mitogen-activated protein kinase kinase 1/2 (MEK1/2) is now a key therapeutic strategy for BRAF-mutant tumors, and therapies based on dual BRAF/MEK inhibition showed significant efficacy in a broad spectrum of BRAF tumors. Nonetheless, BRAF/MEK inhibition therapy is not always effective for BRAF tumor suppression, and significant challenges remain to improve its clinical outcomes. First, certain BRAF tumors have an intrinsic ability to rapidly adapt to the presence of BRAF and MEK1/2 inhibitors by bypassing drug effects via rewired signaling, metabolic, and regulatory networks. Second, almost all tumors initially responsive to BRAF and MEK1/2 inhibitors eventually acquire therapy resistance via an additional genetic or epigenetic alteration(s). Overcoming these challenges requires identifying the molecular mechanism underlying tumor cell resistance to BRAF and MEK inhibitors and analyzing their specificity in different BRAF tumors. This review aims to update this information.

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Tumor Cell Resistance to the Inhibition of BRAF and MEK1/2

Chen,

Park

2023

Preprint

4

0

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BRAF is one of the most frequently mutated oncogenes, with an overall frequency of about 50%. Targeting BRAF and its effector mitogen-activated protein kinase kinase 1/2 (MEK1/2) is now a key therapeutic strategy for BRAF-mutant tumors, and therapies based on dual BRAF/MEK inhibition showed significant efficacy in a broad spectrum of BRAF tumors. Nonetheless, BRAF/MEK inhibition therapy is not always effective for BRAF tumor suppression, and significant challenges remain to improve its clinical outcomes. First, certain BRAF tumors have an intrinsic ability to rapidly adapt to the presence of BRAF and MEK1/2 inhibitors by bypassing drug effects via rewired signaling, metabolic, and regulatory networks. Second, almost all tumors initially responsive to BRAF and MEK1/2 inhibitors eventually acquire therapy resistance via an additional genetic or epigenetic alteration(s). Overcoming these challenges requires identifying the molecular mechanism underlying tumor cell resistance to BRAF and MEK inhibitors and analyzing their specificity in different BRAF tumors. This review aims to update this information.

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The evolution of BRAF-targeted therapies in melanoma: overcoming hurdles and unleashing novel strategies

Imani,

Roozitalab,

Emadi

et al. 2024

Front. Oncol.

1

0

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Melanoma, a highly aggressive form of skin cancer, poses a significant global health burden, with 331,647 new cases and 58,645 deaths reported in 2022. The development of melanoma is influenced by various factors, including sunlight exposure and BRAFV600 mutations that activate the MAPK/ERK pathway. The introduction of BRAF and MEK inhibitors has revolutionized the treatment landscape for melanoma patients. However, innate and acquired therapeutic resistance remains a significant challenge. This review provides a comprehensive overview of the current state of BRAF-targeted therapies in melanoma, highlighting the efficacy and limitations of FDA-approved combinations of BRAF and MEK inhibitors such as vemurafenib, dabrafenib, trametinib, and cobimetinib. The review also explores the off-target effects of BRAF inhibitors on endothelial cells, emphasizing the need for more selective therapies to minimize vascular complications and metastatic potential. The article also discusses potential druggable targets, including ERK5, CD73, ALDH1A1, PLA1A, and DMKN, which are promising in addressing diagnostic hurdles and guiding personalized therapeutic decisions. Recent studies on regorafenib, ERK5 signaling, and CD73 inhibition are highlighted as novel strategies to overcome resistance and improve treatment outcomes. The review also delves into the role of advanced therapeutic tools, such as mRNA vaccines and CRISPR-Cas9, in revolutionizing personalized oncology by targeting specific genetic mutations and enhancing immune responses against melanoma. The ongoing synergy between advancing research, targeted interventions, strategic treatment combinations, and cost-effectiveness evaluations offers a promising pathway to elevate patient outcomes in the persistent battle against melanoma significantly.

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Lessons from clinical trials on triple combination of immune checkpoint inhibitors and BRAF/MEK inhibitors in BRAF-mutant melanoma

Cited by 3 publications

References 16 publications

Tumor Cell Resistance to the Inhibition of BRAF and MEK1/2

Tumor Cell Resistance to the Inhibition of BRAF and MEK1/2

Tumor Cell Resistance to the Inhibition of BRAF and MEK1/2

The evolution of BRAF-targeted therapies in melanoma: overcoming hurdles and unleashing novel strategies

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