Metabolic Adaptations to MEK and CDK4/6 Cotargeting in Uveal Melanoma

Frequent GNAQ and GNA11 mutations in uveal melanoma hyperactivate the MEK–ERK signaling pathway, leading to aberrant regulation of cyclin-dependent kinases (CDK) and cell-cycle progression. MEK inhibitors (MEKi) alone show poor efficacy in uveal melanoma, raising the question of whether downstream targets can be vertically inhibited to provide long-term benefit. CDK4/6 selective inhibitors are FDA-approved in patients with estrogen receptor (ER)–positive breast cancer in combination with ER antagonists/aromatase inhibitors. We determined the effects of MEKi plus CDK4/6 inhibitors (CDK4/6i) in uveal melanoma. In vitro, palbociclib, a CDK4/6i, enhanced the effects of MEKi via downregulation of cell-cycle proteins. In contrast, in vivo CDK4/6 inhibition alone led to cytostasis and was as effective as MEKi plus CDK4/6i treatment at delaying tumor growth. RNA sequencing revealed upregulation of the oxidative phosphorylation (OxPhos) pathway in both MEKi-resistant tumors and CDK4/6i-tolerant tumors. Furthermore, oxygen consumption rate was increased following MEKi + CDK4/6i treatment. IACS-010759, an OxPhos inhibitor, decreased uveal melanoma cell survival in combination with MEKi + CDK4/6i. These data highlight adaptive upregulation of OxPhos in response to MEKi + CDK4/6i treatment in uveal melanoma and suggest that suppression of this metabolic state may improve the efficacy of MEKi plus CDK4/6i combinations.

[1]  R. Deberardinis,et al.  A Novel Mitochondrial Inhibitor Blocks MAPK Pathway and Overcomes MAPK Inhibitor Resistance in Melanoma , 2019, Clinical Cancer Research.

[2]  Michael L. Wang,et al.  Metabolic reprogramming toward oxidative phosphorylation identifies a therapeutic target for mantle cell lymphoma , 2019, Science Translational Medicine.

[3]  G. Schwartz,et al.  Stromal fibroblast growth factor 2 reduces the efficacy of bromodomain inhibitors in uveal melanoma , 2019, EMBO molecular medicine.

[4]  A. Aplin,et al.  Effects of Oncogenic Gαq and Gα11 Inhibition by FR900359 in Uveal Melanoma , 2018, Molecular Cancer Research.

[5]  M. Protopopova,et al.  An inhibitor of oxidative phosphorylation exploits cancer vulnerability , 2018, Nature Medicine.

[6]  M. Keating,et al.  Biological and metabolic effects of IACS-010759, an OxPhos inhibitor, on chronic lymphocytic leukemia cells , 2018, Oncotarget.

[7]  R. Dummer,et al.  In Vivo E2F Reporting Reveals Efficacious Schedules of MEK1/2-CDK4/6 Targeting and mTOR-S6 Resistance Mechanisms. , 2018, Cancer discovery.

[8]  J. McCubrey,et al.  Drug discovery targeting the mTOR pathway. , 2018, Clinical science.

[9]  C. Berking,et al.  Selumetinib in Combination With Dacarbazine in Patients With Metastatic Uveal Melanoma: A Phase III, Multicenter, Randomized Trial (SUMIT). , 2018, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[10]  M. Goetz,et al.  MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  P. Fortina,et al.  Establishment of an orthotopic patient-derived xenograft mouse model using uveal melanoma hepatic metastasis , 2017, Journal of Translational Medicine.

[12]  C. Berking,et al.  Phase 1b/2 trial of ribociclib+binimetinib in metastatic NRAS-mutant melanoma: Safety, efficacy, and recommended phase 2 dose (RP2D). , 2017 .

[13]  A. Aplin,et al.  Dysregulated GPCR Signaling and Therapeutic Options in Uveal Melanoma , 2017, Molecular Cancer Research.

[14]  A. Aplin,et al.  Co-targeting HGF/cMET Signaling with MEK Inhibitors in Metastatic Uveal Melanoma , 2017, Molecular Cancer Therapeutics.

[15]  K. Gelmon,et al.  Palbociclib and Letrozole in Advanced Breast Cancer. , 2016, The New England journal of medicine.

[16]  A. Aplin,et al.  An In Vivo Reporter to Quantitatively and Temporally Analyze the Effects of CDK4/6 Inhibitor-Based Therapies in Melanoma. , 2016, Cancer research.

[17]  A. Bowcock,et al.  Driver Mutations in Uveal Melanoma: Associations With Gene Expression Profile and Patient Outcomes. , 2016, JAMA ophthalmology.

[18]  E. Knudsen,et al.  Metabolic Reprogramming of Pancreatic Cancer Mediated by CDK4/6 Inhibition Elicits Unique Vulnerabilities. , 2016, Cell reports.

[19]  J. Mesirov,et al.  The Molecular Signatures Database Hallmark Gene Set Collection , 2015 .

[20]  J. Sosman,et al.  3300 A phase 1b/2 study of ribociclib (LEE011; CDK4/6 inhibitor) in combination with binimetinib (MEK162; MEK inhibitor) in patients with NRAS-mutant melanoma , 2015 .

[21]  N. Dhomen,et al.  Resistance to BRAF inhibitors induces glutamine dependency in melanoma cells , 2015, Molecular oncology.

[22]  A. Aplin,et al.  Paracrine Effect of NRG1 and HGF Drives Resistance to MEK Inhibitors in Metastatic Uveal Melanoma. , 2015, Cancer research.

[23]  Alexander Lorz,et al.  Emergence of drug tolerance in cancer cell populations: an evolutionary outcome of selection, nongenetic instability, and stress-induced adaptation. , 2015, Cancer research.

[24]  G. McArthur,et al.  Cell cycle control as a promising target in melanoma , 2015, Current opinion in oncology.

[25]  Kakajan Komurov,et al.  Inhibition of mTORC1/2 overcomes resistance to MAPK pathway inhibitors mediated by PGC1α and oxidative phosphorylation in melanoma. , 2014, Cancer research.

[26]  W. Huber,et al.  Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 , 2014, Genome Biology.

[27]  G. Linette,et al.  Effect of selumetinib vs chemotherapy on progression-free survival in uveal melanoma: a randomized clinical trial. , 2014, JAMA.

[28]  Kang Zhang,et al.  Mutant Gq/11 promote uveal melanoma tumorigenesis by activating YAP. , 2014, Cancer cell.

[29]  J. Sosman,et al.  A phase 1b/2 study of LEE011 in combination with binimetinib (MEK162) in patients with NRAS-mutant melanoma: Early encouraging clinical activity. , 2014 .

[30]  H. Rui,et al.  Expression of insulin‐like growth factor‐1 receptor in metastatic uveal melanoma and implications for potential autocrine and paracrine tumor cell growth , 2014, Pigment cell & melanoma research.

[31]  Jun S. Song,et al.  Oncogenic BRAF regulates oxidative metabolism via PGC1α and MITF. , 2013, Cancer cell.

[32]  P. Puigserver,et al.  PGC1α expression defines a subset of human melanoma tumors with increased mitochondrial capacity and resistance to oxidative stress. , 2013, Cancer cell.

[33]  Edgar Brunner,et al.  Nonparametric analysis of longitudinal data in factorial experiments , 2012 .

[34]  Gerald C. Chu,et al.  Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma , 2012, Nature Medicine.

[35]  Rohan Shah,et al.  dlmap: An R Package for Mixed Model QTL and Association Analysis , 2012 .

[36]  Colin N. Dewey,et al.  RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome , 2011, BMC Bioinformatics.

[37]  J. O'Brien,et al.  Mutations in GNA11 in uveal melanoma. , 2010, The New England journal of medicine.

[38]  Ben S. Wittner,et al.  A Chromatin-Mediated Reversible Drug-Tolerant State in Cancer Cell Subpopulations , 2010, Cell.

[39]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[40]  J. Lyons,et al.  Recent progress in targeting the Raf/MEK/ERK pathway with inhibitors in cancer drug discovery. , 2005, Current opinion in pharmacology.

[41]  M. Daly,et al.  PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes , 2003, Nature Genetics.

[42]  Subir Ghosh,et al.  Nonparametric Analysis of Longitudinal Data in Factorial Experiments , 2003, Technometrics.

[43]  Alexander V Penson,et al.  Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma. , 2018, Cancer cell.

[44]  J. Mesirov,et al.  The Molecular Signatures Database (MSigDB) hallmark gene set collection. , 2015, Cell systems.

[45]  Xin Huang,et al.  The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. , 2015, The Lancet. Oncology.

[46]  Thomas R. Gingeras,et al.  STAR: ultrafast universal RNA-seq aligner , 2013, Bioinform..

[47]  G. Barsh,et al.  Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi , 2010 .

[48]  Edgar Brunner,et al.  Nonparametric methods in factorial designs , 2001 .

[49]  R. Scully,et al.  Assessment of metastatic disease status at death in 435 patients with large choroidal melanoma in the Collaborative Ocular Melanoma Study (COMS): COMS report no. 15. , 2001, Archives of ophthalmology.