Mechanisms of Resistance to BRAF-Targeted Melanoma Therapies

Dülgar, Özgecan; Kütük, Tuğçe; Eroglu, Zeynep

doi:10.1007/s40257-020-00572-6

Cited by 15 publications

(13 citation statements)

References 71 publications

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“…Other strategies, such as the use of heat shock protein 90 inhibitors and anti-apoptotic proteins (such as BCL-2), have also been reported to delay the resistance to BRAF inhibitors in melanoma. 37 …”

Section: Discussionmentioning

confidence: 99%

Molecular mechanisms underlying the resistance of BRAF V600E-mutant metastatic colorectal cancer to EGFR/BRAF inhibitors

Wang

et al. 2022

Ther Adv Med Oncol

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Background: Combinatorial inhibition of epidermal growth factor receptor (EGFR) and BRAF shows remarkable clinical benefits in patients with BRAF V600E-mutant metastatic colorectal cancer (mCRC). However, the tumor may inevitably develop resistance to the targeted therapy, thereby limiting the response rate and durability. This study aimed to determine the genetic alterations associated with intrinsic and acquired resistance to EGFR/BRAF inhibitors in BRAF V600E-mutant mCRC. Methods: Targeted sequencing of 520 cancer-related genes was performed in tumor tissues and in plasma samples collected from patients with BRAF V600E-mutant mCRC, who were treated with EGFR/BRAF ± MEK inhibitors, before and after the targeted treatment. Clinical benefit was defined as an objective response or a stable disease lasting longer than the median progression-free survival (PFS). Results: In all, 25 patients with BRAF V600E-mutant mCRC were included in this study. Those with RNF43 mutations ( n = 8) were more likely to achieve clinical benefit from EGFR/BRAF inhibitors than those with wild-type RNF43 (87.5% versus 37.5%, p = 0.034). Genetic alterations in receptor tyrosine kinase genes ( n = 6) were associated with worse PFS ( p = 0.005). Among the 23 patients whose disease progressed after the EGFR/BRAF-targeted therapy, at least one acquired resistance-related mutation was detected in 12 patients. Acquired mutations were most frequently observed in the mitogen-activated protein kinase pathway-related genes ( n = 9), including KRAS (G12D and Q61H/R), NRAS (Q61L/R/K and amplification), BRAF (amplification), and MEK1 (K57T). MET amplification and PIK3R1 Q579fs mutation emerged in three patients and one patient, respectively, after disease progression. Conclusion: Multiple genetic alterations are associated with clinical benefits and resistance to EGFR/BRAF inhibitors in BRAF V600E-mutant mCRC. Our findings provide novel insights into strategies for overcoming resistance to EGFR/BRAF inhibitors in patients with BRAF V600E-mutant mCRC.

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Section: Discussionmentioning

confidence: 99%

Molecular mechanisms underlying the resistance of BRAF V600E-mutant metastatic colorectal cancer to EGFR/BRAF inhibitors

Wang

et al. 2022

Ther Adv Med Oncol

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“…This locus encodes for two different unrelated tumour suppressor proteins, p16 INK4a and p14 ARF , which regulate cell cycle progression through CDK inhibition or the p53-MDM2 pathway, respectively. Although mutations on p16 INK4a are more common in melanoma, genetic alterations affecting p14 ARF often co-occur with p16 INK4a mutations [ 157 ]. p16 INK4a major targets are Cyclin D-CDK4/6 complexes; therefore, the mechanisms through which RASSF1A could compensate p16 loss are likely to be similar to those involving Cyclin D activity regulation.…”

Section: Potential Impact Of Rassf1a Loss On Brafi Targeted Therapy Resistancementioning

confidence: 99%

Resistance to Targeted Therapy and RASSF1A Loss in Melanoma: What Are We Missing?

McKenna

García-Gutiérrez

2021

IJMS

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Melanoma is one of the most aggressive forms of skin cancer and is therapeutically challenging, considering its high mutation rate. Following the development of therapies to target BRAF, the most frequently found mutation in melanoma, promising therapeutic responses were observed. While mono- and combination therapies to target the MAPK cascade did induce a therapeutic response in BRAF-mutated melanomas, the development of resistance to MAPK-targeted therapies remains a challenge for a high proportion of patients. Resistance mechanisms are varied and can be categorised as intrinsic, acquired, and adaptive. RASSF1A is a tumour suppressor that plays an integral role in the maintenance of cellular homeostasis as a central signalling hub. RASSF1A tumour suppressor activity is commonly lost in melanoma, mainly by aberrant promoter hypermethylation. RASSF1A loss could be associated with several mechanisms of resistance to MAPK inhibition considering that most of the signalling pathways that RASSF1A controls are found to be altered targeted therapy resistant melanomas. Herein, we discuss resistance mechanisms in detail and the potential role for RASSF1A reactivation to re-sensitise BRAF mutant melanomas to therapy.

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“…In addition, the loss of an acquired BRAF V600E mutation has not previously been reported in melanoma. 10 Protein mTOR inhibitors have broad noncancer indications, such as rejection and vascular malformations, but have limited use in cancer. 11 They are indicated for advanced renal cell cancer 12,13 and tuberous sclerosis complex associated tumors 14,15 and have showed some activity in breast cancer, 16,17 lymphoma, 18,19 and neuroendocrine tumors.…”

Section: E T T E R T O T H E E D I T O R Secondary Histiocytic Sarcom...mentioning

confidence: 99%

Secondary histiocytic sarcoma with BRAF^V600E mutation responsive to MAPK‐targeted therapy presenting with recurrence with mTOR mutation responsive to mTOR‐targeted therapy

Venkataraman

Massoth

Sullivan

et al. 2021

Pediatric Blood & Cancer

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Mechanisms of Resistance to BRAF-Targeted Melanoma Therapies

Cited by 15 publications

References 71 publications

Molecular mechanisms underlying the resistance of BRAF V600E-mutant metastatic colorectal cancer to EGFR/BRAF inhibitors

Molecular mechanisms underlying the resistance of BRAF V600E-mutant metastatic colorectal cancer to EGFR/BRAF inhibitors

Resistance to Targeted Therapy and RASSF1A Loss in Melanoma: What Are We Missing?

Secondary histiocytic sarcoma with BRAF^V600E mutation responsive to MAPK‐targeted therapy presenting with recurrence with mTOR mutation responsive to mTOR‐targeted therapy

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Mechanisms of Resistance to BRAF-Targeted Melanoma Therapies

Cited by 15 publications

References 71 publications

Molecular mechanisms underlying the resistance of BRAF V600E-mutant metastatic colorectal cancer to EGFR/BRAF inhibitors

Molecular mechanisms underlying the resistance of BRAF V600E-mutant metastatic colorectal cancer to EGFR/BRAF inhibitors

Resistance to Targeted Therapy and RASSF1A Loss in Melanoma: What Are We Missing?

Secondary histiocytic sarcoma with BRAFV600E mutation responsive to MAPK‐targeted therapy presenting with recurrence with mTOR mutation responsive to mTOR‐targeted therapy

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Secondary histiocytic sarcoma with BRAF^V600E mutation responsive to MAPK‐targeted therapy presenting with recurrence with mTOR mutation responsive to mTOR‐targeted therapy