<i>BRAF</i> Gene Copy Number and Mutant Allele Frequency Correlate with Time to Progression in Metastatic Melanoma Patients Treated with MAPK Inhibitors

Stagni, Camilla; Zamuner, Carolina; Elefanti, Lisa; Zanin, Tiziana; Bianco, Paola Del; Sommariva, Antonio; Fabozzi, Alessio; Pigozzo, Jacopo; Mocellin, Simone; Montesco, Maria Cristina; Chiarion-Sileni, Vanna; Nicolo, Arcangela De; Menin, Chiara

doi:10.1158/1535-7163.mct-17-1124

Cited by 27 publications

(27 citation statements)

References 37 publications

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“…In melanoma patients, decreased BRAF allelic frequency is associated with a poorer clinical outcome to BRAF inhibition and combined BRAF/MEK inhibition (Lebbé et al, 2014;Stagni et al, 2018). The proposed mechanism behind this response is paradoxical MAPK pathway activation due to a higher wild-type allele frequency.…”

Section: Discussionmentioning

confidence: 99%

Identifying the ErbB/MAPK Signaling Cascade as a Therapeutic Target in Canine Bladder Cancer

et al. 2019

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Canine transitional cell carcinoma (TCC) of the bladder accounts for 2% of diagnosed canine cancers. Most TCCs are inoperable and unresponsive to traditional chemotherapy. Median survival time is typically less than a year for all treatments indicating a need for more effective therapies. Recent studies have discovered that approximately 70% of canine TCCs harbor mutations in the proto‐oncogene BRAF, a kinase involved in the mitogen‐activated protein kinase (MAPK) pathway that controls cell proliferation, differentiation, and apoptosis. BRAF mutations are present in several human cancers, most of which exhibit adaptive or intrinsic resistance to BRAF‐targeted inhibitors. The goals of this study were to (1) further characterize the role of mutant BRAF in canine TCC and (2) determine whether inhibition of the MAPK pathway alone or in combination with other gene targets may be an effective therapy for TCC treatment. Analysis of ERK1/2 phosphorylation following serum starvation indicates that TCC cell lines exhibit constitutive MAPK pathway activation independent of their BRAF mutation status. MAPK activity was further quantified using gene expression analysis of ten MAPK target genes, revealing that TCC cell lines have significantly higher MAPK pathway activity compared to other canine cancer cell lines. These data suggest a causative role for MAPK signaling in TCC pathogenesis. To determine whether the MAPK pathway could be a therapeutic target for TCC treatment we assessed the effect of BRAF and MEK inhibition on TCC cell proliferation and ERK1/2 phosphorylation. Four BRAF mutant human cell lines with varying degrees of sensitivity to BRAF‐targeted agents were used to determine the relative sensitivity of canine TCC cell lines. BRAF mutant TCC cell lines were sensitive to BRAF inhibition with the “paradox‐breaking” inhibitor PLX7904 (IC50: 0.2–1.2μM), but not vemurafenib (IC50: 7–21μM). Both BRAF wild type and mutant TCC cell lines were sensitive to MEK inhibition with selumetinib (IC50: 15–420nM) and trametinib (IC50: 0.4–8nM). ERK1/2 phosphorylation decreased after 6‐hour treatments with MAPK inhibitors, but rebounded by 24 hours suggesting the presence of resistance mechanisms. Microarray analysis indicated that the ErbB family of receptors and ligands are up‐regulated in TCC cell lines relative to other canine cancer cell lines (fold‐change > 2, q < 0.05). Combined BRAF and ErbB inhibition synergized in the BRAF mutant Bliley TCC cell line, while combined MEK and ErbB inhibition synergized in both Bliley and BRAF wild type Kinsey cells. These findings suggest that targeting ErbB receptors with MAPK inhibition is a potential therapy for canine TCC treatment. Additionally, our data indicate that canine TCC may serve as a naturally‐occurring model for the study of resistance mechanisms to MAPK inhibition in human cancers. Support or Funding Information Morris Animal Foundation, Shipley University Chair in Comparative Oncology This abstract is from the Experimental Biology 2019 Meeting. There is no full text artic...

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Section: Discussionmentioning

confidence: 99%

Identifying the ErbB/MAPK Signaling Cascade as a Therapeutic Target in Canine Bladder Cancer

et al. 2019

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“…The wide peak annotated by HIPK2 and TBXAS1 contains 72 genes, including BRAF. BRAF amplification is a mechanism of acquired resistance to BRAF inhibitors in BRAFV600E melanomas [56,57,58,59]. We found that patients harboring BRAF-M and HIPK2/TBXAS1-A had shorter progression-free intervals (PFI) compared to patients harboring BRAF-M without HIPK2/TBXAS1-A (cox-ph P = 0.016, Table 4, Figure 5).…”

Section: Novel Melanoma Combinations Detected By Crsomentioning

confidence: 87%

Identifying Modules of Cooperating Cancer Drivers

Klein

Cannataro

Townsend

et al. 2020

Preprint

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AbstractIdentifying cooperating modules of driver alterations can provide biological insights to cancer causation and would advance the development of effective personalized treatments. We present Cancer Rule-Set Optimization (CRSO) for inferring the combinations of alterations that cooperate to drive tumor formation in individual patients. Application to 19 TCGA cancer types found a mean of 11 core driver combinations per cancer, comprising 2-6 alterations per combination, and accounting for a mean of 70% of samples per cancer. CRSO departs from methods based on statistical cooccurrence, which we demonstrate is a suboptimal criterion for investigating driver cooperation. CRSO identified well-studied driver combinations that were not detected by other approaches and nominated novel combinations that correlate with clinical outcomes in multiple cancer types. Novel synergies were identified in NRAS-mutant melanomas that may be therapeutically relevant. Core driver combinations involving NFE2L2 mutations were identified in four cancer types, supporting the therapeutic potential of NRF2 pathway inhibition. CRSO is available at https://github.com/mikekleinsgit/CRSO/.

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“…Moreover, the choice and use of techniques able to quantify the mutant allele frequency of BRAF gene is important since it is reported to influence the clinical efficacy of the BRAF/MEK inhibitors treatments. So, quantitative analysis of the BRAF gene could be useful to select the melanoma patients who are most likely to benefit from target therapy (Stagni et al, 2018 ). In addition, intertumoral and intratumoral heterogeneity could lead to misinterpretation of BRAF mutational status; this is especially important if testing is performed on primary specimens, or micromestasis, when abundant metastatic lesions are unavailable.…”

Section: Discussionmentioning

confidence: 99%

The Current State of Molecular Testing in the BRAF-Mutated Melanoma Landscape

Vanni

Tanda

Spagnolo

et al. 2020

Front. Mol. Biosci.

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The incidence of melanoma, among the most lethal cancers, is widespread and increasing. Metastatic melanoma has a poor prognosis, representing about 90% of skin cancer mortality. The increased knowledge of tumor biology and the greater understanding of the immune system role in the anti-tumor response has allowed us to develop a more rational approach to systemic therapies. The discovery of activating BRAF mutations in half of all melanomas has led to the development of molecularly targeted therapy with BRAF and MEK inhibitors, which dramatically improved outcomes of patients with stage IV BRAF-mutant melanoma. More recently, the results of clinical phase III studies conducted in the adjuvant setting led to the combined administration of BRAF and MEK inhibitors also in patients with resected high-risk melanoma (stage III). Therefore, BRAF mutation testing has become a priority to determine the oncologist's choice and course of therapy. In this review, we will report the molecular biology-based strategies used for BRAF mutation detection with the main advantages and disadvantages of the most commonly used diagnostic strategies. The timing of such molecular assessment in patients with cutaneous melanoma will be discussed, and we will also examine considerations and approaches for accurate and effective BRAF testing.

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BRAF Gene Copy Number and Mutant Allele Frequency Correlate with Time to Progression in Metastatic Melanoma Patients Treated with MAPK Inhibitors

Cited by 27 publications

References 37 publications

Identifying the ErbB/MAPK Signaling Cascade as a Therapeutic Target in Canine Bladder Cancer

Identifying the ErbB/MAPK Signaling Cascade as a Therapeutic Target in Canine Bladder Cancer

Identifying Modules of Cooperating Cancer Drivers

The Current State of Molecular Testing in the BRAF-Mutated Melanoma Landscape

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