MEK Inhibition In Melanoma Research Articles

Abstract 5869: Investigation of molecular alterations associated with double resistance to BRAF and MEK inhibition in melanoma

Abstract More than 50% of melanomas harbor activating BRAF kinase mutations, with BRAFV600E representing more than 90% of BRAF mutations. Inhibition of mutant BRAF by BRAF inhibitors (BRAFi) in patients with advanced melanoma yields a remarkable initial clinical response. Limited duration response and disease recurrence of inhibitors occurs due to acquired drug resistance. Recently identified mechanisms of MAPK hyperactivation in acquired resistance to BRAFi have encouraged clinicians to employ a combination of BRAF and MAPK inhibitors to block the MAPK signaling pathway more effectively. However, most patients treated with this combination therapy still relapse due to de novo drug resistance. Therefore, innovative strategies are still necessary to improve the precision and durability of anti-melanoma therapies. To investigate the mechanism of both BRAFi and MEKi resistance (double resistance, DR) in mutant BRAF melanomas, we have developed models from four human melanoma cell lines to explore the hypothesis that molecular alterations are related to double resistance to BRAFi and MEKi in melanoma. We have found that BRAFi-MEKi double-resistant models exhibit distinct differences in morphology and growth kinetics. Specifically, BRAFi-MEKi double-resistant human melanomas express a higher level of FGFb and PAI-1 expression. We confirmed that overexpression of FGFb and PAI-1 in parental cells could increase the ability to resist BRAF and MEK inhibition. Additionally, we discovered that decreased expression of FGFb and PAI-1, via knock-down, inhibition, or CRISPR in double resistant cells, can restore cell sensitivity to treatments of BRAFi and MEKi. To further elucidate the role of FGFb and PAI-1 on resistant melanoma, we have extended our scope to in vivo mouse xenograft models. Our findings uncovered the mechanism of how melanoma cells can escape BRAFi and MEKi attacks and offer a rational strategy to guide future clinical treatments. Citation Format: Armond J. Isaak, GeGe R. Clements, Lei Huang, Yifei Qin, Qiang Zho, Glenn Merlino, Yanlin Yu. Investigation of molecular alterations associated with double resistance to BRAF and MEK inhibition in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5869.

Encorafenib, Binimetinib and Cetuximab Combined Therapy for Patients with BRAFV600E Mutant Metastatic Colorectal Cancer

Approximately 10-15% of colorectal cancers (CRCs) harbor an activating BRAF mutation, leading to tumor growth promotion by activation of the mitogen-activated protein kinases pathway. BRAFV600E mutations are prognostic for treatment failure after first-line systemic therapy in the metastatic setting. In contrast to the efficacy of combined BRAF and MEK inhibition in melanoma, BRAFV600E mutant CRC is intrinsically unresponsive due to upregulation of HER/EGFR. However, combining the EGFR inhibitor cetuximab, the BRAF inhibitor encorafenib and the MEK inhibitor binimetinib improves overall survival. This review discusses the current treatment field for patients with BRAFV600E mutant metastatic CRC and summarizes the pharmacology, efficacy and safety of the novel doublet and triplet therapies consisting of encorafenib and cetuximab with or without binimetinib.

Efficacy and safety of BRAF inhibition alone versus combined BRAF and MEK inhibition in melanoma: a meta-analysis of randomized controlled trials.

Recent clinical studies have shown that combination therapy of BRAF and MEK inhibition provides more survival benefit than BRAF inhibition monotherapy. However, the adverse events due to BRAF and MEK inhibitors impact the physical comfort and social life of patients. Thus, in this study we have undertaken a meta-analysis of randomized controlled trials to compare the efficacy and adverse events risk between monotherapy and combination therapy. We identified the relevant studies by searching PubMed, EMBASE and Google scholar databases, between the year January 2000 and May 2016. Based on the heterogeneity, the fixed- or random-effects models were employed to analyze the efficacy and the incidence rate of adverse events. In addition, the subgroup analyses were conducted to overcome the effects of heterogeneity. Finally, our study included five RCTs, involving 1730 patients for this meta-analysis. The fixed-effects model demonstrated that combination therapy of BRAF and MEK inhibition provided more survival benefit in terms of ORR, PFS and OS (P < 0.00001). But, the combination therapy also significantly increased the incidences of pyrexia, chills, vomiting, chorioretinopathy, retinal detachment, hypertension, night sweats, increased aspartate aminotransferase and creatine kinase levels (P < 0.05) as compared to monotherapy. But, based on the significantly better survival outcomes, the combined BRAF and MEK inhibition will obviously be the mainstay therapy for the BRAF V600-mutant melanoma. However, a set of adverse events should be paid attention when physicians consider combination therapy.

Type I IFN Activity Predicts Response to MEK Inhibition in Melanoma

Abstract IFNα/β enhances the cytotoxicity of MEK inhibition in melanoma cells with low basal STAT1 activity.

Let a Hundred Flowers Bloom: The Role of Context Dependence in Creating Phenotypic Diversity following Targeted Therapy

Using a newly developed computational platform, COSPER, Litvin etal. (2015) identify context-dependent interactions between MEK and interferon signaling that underlie sensitivity and resistance to MEK inhibition in melanoma.

Inhibition of HSP90 by AT13387 delays the emergence of resistance to BRAF inhibitors and overcomes resistance to dual BRAF and MEK inhibition in melanoma models.

Emergence of clinical resistance to BRAF inhibitors, alone or in combination with MEK inhibitors, limits clinical responses in melanoma. Inhibiting HSP90 offers an approach to simultaneously interfere with multiple resistance mechanisms. Using the HSP90 inhibitor AT13387, which is currently in clinical trials, we investigated the potential of HSP90 inhibition to overcome or delay the emergence of resistance to these kinase inhibitors in melanoma models. In vitro, treating vemurafenib-sensitive cells (A375 or SK-MEL-28) with a combination of AT13387 and vemurafenib prevented colony growth under conditions in which vemurafenib treatment alone generated resistant colonies. In vivo, when AT13387 was combined with vemurafenib in a SK-MEL-28, vemurafenib-sensitive model, no regrowth of tumors was observed over 5 months, although 2 of 7 tumors in the vemurafenib monotherapy group relapsed in this time. Together, these data suggest that the combination of these agents can delay the emergence of resistance. Cell lines with acquired vemurafenib resistance, derived from these models (A375R and SK-MEL-28R) were also sensitive to HSP90 inhibitor treatment; key clients were depleted, apoptosis was induced, and growth in 3D culture was inhibited. Similar effects were observed in cell lines with acquired resistance to both BRAF and MEK inhibitors (SK-MEL-28RR, WM164RR, and 1205LuRR). These data suggest that treatment with an HSP90 inhibitor, such as AT13387, is a potential approach for combating resistance to BRAF and MEK inhibition in melanoma. Moreover, frontline combination of these agents with an HSP90 inhibitor could delay the emergence of resistance, providing a strong rationale for clinical investigation of such combinations in BRAF-mutated melanoma.

Abstract 4761: Defining the adaptive kinome response to BRAF and MEK inhibition in melanoma

Abstract Early clinical studies have shown that concurrent administration of BRAF and MEK inhibitors, dabrafenib and trametinib, is more active in patients with BRAFV600E/K melanoma than either single agent alone. Even though the combination of BRAF/MEK inhibitors is initially highly effective in treating melanoma in a subset of patients, progression to resistance ultimately occurs–commonly via reactivation of the BRAF/MEK/ERK pathway. Therefore, therapeutic strategies to counter primary resistance and prevent the emergence of secondary resistance are needed. Following pharmacological or progressive genetic perturbations, dynamic and system-wide adaptive changes (“reprogramming”) in the expression and activity of multiple kinases (collectively termed the kinome) clearly occur in tumor cells. Rich networks of serine/threonine and tyrosine kinases, many of which are understudied, are integrated into the signaling systems controlled by oncogenes known to drive melanoma. Thus, a comprehensive understanding of the kinome at baseline, during the adaptive response to kinase inhibitor treatment, and in the context of acquired resistance is critical. We use Multiplexed Inhibitor Beads (MIBs), mixtures of covalently immobilized, linker-adapted kinase inhibitors coupled with mass spectrometry (MS), to assess changes in activation of kinases in untreated samples, during acute inhibition of BRAF and/or MEK and in the context of acquired resistance. Our enhanced MIB/MS technology allows us to study over 75-80% of the expressed kinome (and numerous lipid and metabolic kinases) simultaneously using lysates from cell lines, genetically engineered mouse model (GEMM) tumors, patient-derived xenografts or human melanoma. We have identified several kinases (e.g. PDGFRβ, DDR1, MAP3K1) that are activated upon acute treatment with dabrafenib, trametinib, or dabrafenib/trametinib as well as in drug-resistant human melanoma cells and BRAFV600E/PTEN-/- GEMM-derived tumors and cell lines. Thus, studies using MIB/MS to measure dynamic kinome responses have identified kinases that have not been previously shown to be involved in the adaptive response to BRAF and/or MEK inhibition. We are currently targeting kinases involved in adaptive kiome reprogramming, pharmacologically or by RNAi, to determine whether their activation leads to vulnerability. This work will lead to the identification of novel and rationally predicted therapies for patients with advanced melanoma. Citation Format: Steven P. Angus, Timothy J. Stuhlmiller, Rachel Reuther, Trang T. Pham, Deborah A. Granger, David B. Darr, Jamie L. Jordan, Stergios J. Moschos, Gary L. Johnson, Norman E. Sharpless. Defining the adaptive kinome response to BRAF and MEK inhibition in melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4761. doi:10.1158/1538-7445.AM2014-4761

Melanoma: immune checkpoint blockade story gets better

The 10-year survival for patients with metastatic melanoma is less than 10%. 1 Balch CM Gershenwald JE Soong SJ et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009; 27: 6199-6206 Crossref PubMed Scopus (3603) Google Scholar After decades of failed attempts to improve treatment outcomes in patients with this disease, 2 Bhatia S Tykodi SS Thompson JA Treatment of metastatic melanoma: an overview. Oncology. 2009; 23: 488-496 PubMed Google Scholar the recent successes with ipilimumab and the inhibitors of BRAF and MEK (vemurafenib, dabrafenib, and trametinib) have ushered in a new era in systemic therapy. 3 Bhatia S Thompson JA Systemic therapy for metastatic melanoma in 2012: dawn of a new era. J Natl Compr Canc Netw. 2012; 10: 403-412 PubMed Google Scholar , 4 Hodi FS O'Day SJ McDermott DF et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010; 363: 711-723 Crossref PubMed Scopus (10966) Google Scholar , 5 Chapman PB Hauschild A Robert C et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011; 364: 2507-2516 Crossref PubMed Scopus (6022) Google Scholar , 6 Flaherty KT Infante JR Daud A et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012; 367: 1694-1703 Crossref PubMed Scopus (2101) Google Scholar , 7 Flaherty KT Robert C Hersey P et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012; 367: 107-114 Crossref PubMed Scopus (1681) Google Scholar These breakthroughs have not only provided more treatment options for patients with melanoma, but have also spurred the investigation of a new generation of drugs for cancer therapy. In The Lancet, Caroline Robert and colleagues 8 Robert C Ribas A Wolchok JD et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014; (published online July 15.)http://dx.doi.org/10.1016/S0140-6736(14)60958-2 PubMed Google Scholar report the results of programmed-death-receptor-1 (PD-1) blockade with pembrolizumab (MK-3475) in patients with melanoma previously treated with an anti-cytotoxic T-lymphocyte-associated-antigen-4 (CTLA-4) antibody ipilimumab; these findings are another important advance in the rapidly evolving landscape of cancer immunotherapy. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trialThe results suggest that pembrolizumab at a dose of 2 mg/kg or 10 mg/kg every 3 weeks might be an effective treatment in patients for whom there are few effective treatment options. Full-Text PDF

Targeted chemotherapy of metastatic melanoma: the impact of tumor cell heterogeneity

Evaluation of: Flaherty KT, Infante JR, Daud A et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N. Engl. J. Med. 367(18), 1694–1703 (2012).The treatment of metastatic melanoma with BRAF inhibitors initially gave dramatic results compared with standard chemotherapy with significant progression-free survival times. Unfortunately, within a matter of months, the melanomas become refractory to anti-BRAF-targeted therapy and some patients experience toxicity in the form of primary cutaneous squamous cell carcinomas. While recent reports of dual therapy targeting the MAPK pathway (e.g., dabrafenib and trametinib) show increased response rates and less toxicity, it is not apparent that overall survival has been significantly impacted. While targeted therapy has significantly altered the management of melanoma, novel approaches and strategies will likely have to be employed to counter melanoma cell heterogeneity and the selection of resistant clones.

Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations

BackgroundResistance to therapy with BRAF kinase inhibitors is associated with reactivation of the mitogen-activated protein kinase (MAPK) pathway. To address this problem, we conducted a phase 1 and 2 trial of combined treatment with dabrafenib, a selective BRAF inhibitor, and trametinib, a selective MAPK kinase (MEK) inhibitor.MethodsIn this open-label study involving 247 patients with metastatic melanoma and BRAF V600 mutations, we evaluated the pharmacokinetic activity and safety of oral dabrafenib (75 or 150 mg twice daily) and trametinib (1, 1.5, or 2 mg daily) in 85 patients and then randomly assigned 162 patients to receive combination therapy with dabrafenib (150 mg) plus trametinib (1 or 2 mg) or dabrafenib monotherapy. The primary end points were the incidence of cutaneous squamous-cell carcinoma, survival free of melanoma progression, and response. Secondary end points were overall survival and pharmacokinetic activity.ResultsDose-limiting toxic effects were infrequently observed in patients receiving combination therapy with 150 mg of dabrafenib and 2 mg of trametinib (combination 150/2). Cutaneous squamous-cell carcinoma was seen in 7% of patients receiving combination 150/2 and in 19% receiving monotherapy (P=0.09), whereas pyrexia was more common in the combination 150/2 group than in the monotherapy group (71% vs. 26%). Median progression-free survival in the combination 150/2 group was 9.4 months, as compared with 5.8 months in the monotherapy group (hazard ratio for progression or death, 0.39; 95% confidence interval, 0.25 to 0.62; P<0.001). The rate of complete or partial response with combination 150/2 therapy was 76%, as compared with 54% with monotherapy (P=0.03).ConclusionsDabrafenib and trametinib were safely combined at full monotherapy doses. The rate of pyrexia was increased with combination therapy, whereas the rate of proliferative skin lesions was nonsignificantly reduced. Progression-free survival was significantly improved. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01072175.)