MEK inhibitors under development for treatment of non-small-cell lung cancer

References

• Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017 Jan;67(1):7–30.
   PubMed Web of Science ®Google Scholar
• Houston KA, Henley SJ, Li J, et al. Patterns in lung cancer incidence rates and trends by histologic type in the United States, 2004-2009. Lung Cancer. 2014 Oct;86(1):22–28.
   PubMed Web of Science ®Google Scholar
• Govindan R, Ding L, Griffith M, et al. Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell. 2012 Sep 14;150(6):1121–1134.
   PubMed Web of Science ®Google Scholar
• Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010 Jun 24;362(25):2380–2388.
   PubMed Web of Science ®Google Scholar
• Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010 Feb;11(2):121–128.
   PubMed Web of Science ®Google Scholar
• Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012 Mar;13(3):239–246.
   PubMed Web of Science ®Google Scholar
• Shaw AT, Ou SH, Bang YJ, et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med. 2014 Nov 20;371(21):1963–1971.
   PubMed Web of Science ®Google Scholar
• Yang JC, Wu YL, Schuler M, et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015 Feb;16(2):141–151.
   PubMed Web of Science ®Google Scholar
• Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011 Aug;12(8):735–742.
   PubMed Web of Science ®Google Scholar
• Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014 Dec 04;371(23):2167–2177.
   PubMed Web of Science ®Google Scholar
• Arrieta O, Cardona AF, Corrales L, et al. The impact of common and rare EGFR mutations in response to EGFR tyrosine kinase inhibitors and platinum-based chemotherapy in patients with non-small cell lung cancer. Lung Cancer. 2015 Feb;87(2):169–175.
   PubMed Web of Science ®Google Scholar
• Sullivan I, Planchard D. ALK inhibitors in non-small cell lung cancer: the latest evidence and developments. Ther Adv Med Oncol. 2016 Jan;8(1):32–47.
   PubMed Web of Science ®Google Scholar
• Molina JR, Adjei AA. The Ras/Raf/MAPK pathway. J Thorac Oncol. 2006 Jan 01; 1(1):7–9.
   PubMed Web of Science ®Google Scholar
• Dhillon AS, Hagan S, Rath O, et al. MAP kinase signalling pathways in cancer. Oncogene. 2007 May 14;26(22):3279–3290.
   PubMed Web of Science ®Google Scholar
• Eberhard DA, Johnson BE, Amler LC, et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non–small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol. 2005;23(25):5900–5909.
   PubMed Web of Science ®Google Scholar
• Slebos RJ, Kibbelaar RE, Dalesio O, et al. K-ras oncogene activation as a prognostic marker in adenocarcinoma of the lung. New England J Med. 1990;323(9):561–565.
   PubMed Web of Science ®Google Scholar
• Nelson HH, Christiani DC, Mark EJ, et al. Implications and prognostic value of K-ras mutation for early-stage lung cancer in women. J Natl Cancer Inst. 1999;91(23):2032–2038.
   PubMed Web of Science ®Google Scholar
• Kim C, Giaccone G. Lessons learned from BATTLE-2 in the war on cancer: the use of Bayesian method in clinical trial design. Ann Transl Med. 2016 Dec;4(23):466.
   PubMed Web of Science ®Google Scholar
• Ostrem JM, Peters U, Sos ML, et al. K-Ras (G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013;503(7477):548–551.
   PubMed Web of Science ®Google Scholar
• Long GV, Menzies AM, Nagrial AM, et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol. 2011;29(10):1239–1246.
   PubMed Web of Science ®Google Scholar
• Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. New England J Med. 2011;364(26):2507–2516.
   PubMed Web of Science ®Google Scholar
• Hauschild A, Grob -J-J, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. The Lancet. 2012;380(9839):358–365.
   PubMed Web of Science ®Google Scholar
• Cardarella S, Ogino A, Nishino M, et al. Clinical, pathologic, and biologic features associated with BRAF mutations in non–small cell lung cancer. Clin Cancer Res. 2013 Aug 13 21:06:19;19:4532–4540.
   PubMed Web of Science ®Google Scholar
• Marchetti A, Felicioni L, Malatesta S, et al. Clinical features and outcome of patients with non–small-cell lung cancer harboring BRAF mutations. J Clin Oncol. 2011;29(26):3574–3579.
   PubMed Web of Science ®Google Scholar
• Brustugun OT, Khattak AM, Tromborg AK, et al. BRAF-mutations in non-small cell lung cancer. Lung Cancer. 2014 Apr;84(1):36–38.
   PubMed Web of Science ®Google Scholar
• Planchard D, Kim TM, Mazieres J, et al. Dabrafenib in patients with BRAF V600E-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016;17(5):642–650.
   PubMed Web of Science ®Google Scholar
• Hyman DM, Puzanov I, Subbiah V, et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. New England J Med. 2015;373(8):726–736.
   PubMed Web of Science ®Google Scholar
• Caunt CJ, Sale MJ, Smith PD, et al. MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road. Nature Reviews Cancer. 2015;15(10):577.
   PubMed Web of Science ®Google Scholar
• Roskoski R Jr. ERK1/2 MAP kinases: structure, function, and regulation. Pharmacol Res. 2012 Aug;66(2):105–143.
   PubMed Web of Science ®Google Scholar
• Arcila ME, Drilon A, Sylvester BE, et al. MAP2K1 (MEK1) mutations define a distinct subset of lung adenocarcinoma associated with smoking. Clin Cancer Res. 2015 Apr 15;21(8):1935–1943.
   PubMed Web of Science ®Google Scholar
• Marks JL, Gong Y, Chitale D, et al. Novel MEK1 mutation identified by mutational analysis of epidermal growth factor receptor signaling pathway genes in lung adenocarcinoma. Cancer Res. 2008 Jul 15;68(14):5524–5528.
   PubMed Web of Science ®Google Scholar
• Ohren JF, Chen H, Pavlovsky A, et al. Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nat Struct Mol Biol. 2004 Dec;11(12):1192–1197.
   PubMed Web of Science ®Google Scholar
• Solit DB, Garraway LA, Pratilas CA, et al. BRAF mutation predicts sensitivity to MEK inhibition. Nature. 2006;439(7074):358.
   PubMed Web of Science ®Google Scholar
• Engelman JA, Chen L, Tan X, et al. Effective use of PI3K and MEK inhibitors to treat mutant KRAS G12D and PIK3CA H1047R murine lung cancers. Nat Med. 2008;14(12):1351–1356.
   PubMed Web of Science ®Google Scholar
• Wee S, Jagani Z, Xiang KX, et al. PI3K pathway activation mediates resistance to MEK inhibitors in KRAS mutant cancers. Cancer Res. 2009;69(10):4286–4293.
   PubMed Web of Science ®Google Scholar
• Corcoran RB, Cheng KA, Hata AN, et al. Synthetic lethal interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS mutant cancer models. Cancer Cell. 2013;23(1):121–128.
   PubMed Web of Science ®Google Scholar
• Yeh TC, Marsh V, Bernat BA, et al. Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor. Clin Cancer Res. 2007 Mar 01;13(5):1576–1583.
   PubMed Web of Science ®Google Scholar
• Davies BR, Logie A, McKay JS, et al. AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models. Mol Cancer Ther. 2007 Aug 15 10:53:37;6:2209–2219.
   PubMed Web of Science ®Google Scholar
• Lee P, Wallace E, Yeh T, et al. ARRY-142886, a potent and selective MEK inhibitor: III) efficacy in murine xenograft models correlates with decreased ERK phosphorylation. Cancer Res. 2014 Oct 23 11:54:47;64:897.
   Google Scholar
• Adjei AA, Cohen RB, Franklin W, et al. Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 Inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol. 2008;26(13):2139–2146.
   PubMed Web of Science ®Google Scholar
• Hainsworth JD, Cebotaru CL, Kanarev V, et al. A phase II, open-label, randomized study to assess the efficacy and safety of AZD6244 (ARRY-142886) versus pemetrexed in patients with non-small cell lung cancer who have failed one or two prior chemotherapeutic regimens. J Thorac Oncol. 2010 Oct;5(10):1630–1636.
   PubMed Web of Science ®Google Scholar
• Lopez-Chavez A, Thomas A, Rajan A, et al. Molecular profiling and targeted therapy for advanced thoracic malignancies: a biomarker-derived, multiarm, multihistology phase II basket trial. J Clin Oncol. 2015 Mar 20;33(9):1000–1007.
   PubMed Web of Science ®Google Scholar
• Janne PA, Shaw AT, Pereira JR, et al. Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol. 2013 Jan;14(1):38–47.
   PubMed Web of Science ®Google Scholar
• Janne PA, van den Heuvel MM, Barlesi F, et al. Selumetinib plus docetaxel compared with docetaxel alone and progression-free survival in patients with KRAS-mutant advanced non-small cell lung cancer: the SELECT-1 randomized clinical trial. Jama. 2017 May 09;317(18):1844–1853.
   PubMed Web of Science ®Google Scholar
• Carter CA, Rajan A, Keen C, et al. Selumetinib with and without erlotinib in KRAS mutant and KRAS wild-type advanced nonsmall-cell lung cancer. Ann Oncology. 2016 Apr;27(4):693–699.
   PubMed Web of Science ®Google Scholar
• Gilmartin AG, Bleam MR, Groy A, et al. GSK1120212 (JTP-74057) is an inhibitor of MEK activity and activation with favorable pharmacokinetic properties for sustained in vivo pathway inhibition. Clin Cancer Res. 2011;17:989–1000, clincanres. 2200.010
   PubMed Web of Science ®Google Scholar
• Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. New England J Med. 2012;367(2):107–114.
   PubMed Web of Science ®Google Scholar
• Long GV, Stroyakovskiy D, Gogas H, et al. Dabrafenib and trametinib versus dabrafenib and placebo for VAL600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. The Lancet. 2015 Aug 01;386(9992):444–451.
   PubMed Web of Science ®Google Scholar
• Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. New England J Med. 2015;372(1):30–39.
   PubMed Web of Science ®Google Scholar
• Blumenschein GR Jr., Smit EF, Planchard D, et al. A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small-cell lung cancer (NSCLC)dagger. Ann Oncology. 2015 May;26(5):894–901.
   PubMed Web of Science ®Google Scholar
• Planchard D, Besse B, Groen HJ, et al. Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol. 2016 Jul;17(7):984–993.
   PubMed Web of Science ®Google Scholar
• Planchard D, Besse B, Kim TM, et al. Updated survival of patients (PTS) with previously treated BRAF V600E–mutant advanced non-small cell lung cancer (NSCLC) who received dabrafenib (D) or D+ trametinib (T) in the phase II BRF113928 study. Am Soc Clin Oncol. 2017;35(15_suppl): 9075–9075.
   Web of Science ®Google Scholar
• Planchard D, Smit EF, Groen HJM, et al. Dabrafenib plus trametinib in patients with previously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol. 2017 Oct;18(10):1307–1316.
   PubMed Web of Science ®Google Scholar
• Turke AB, Song Y, Costa C, et al. MEK inhibition leads to PI3K/AKT activation by relieving a negative feedback on ERBB receptors. Cancer Res. 2012 Jul 01; 21:06:54;72:3228–3237.
   PubMed Web of Science ®Google Scholar
• Tolcher AW, Bendell JC, Papadopoulos KP, et al. A phase IB trial of the oral MEK inhibitor trametinib (GSK1120212) in combination with everolimus in patients with advanced solid tumors. Ann Oncol. 2015;26(1):58–64.
   PubMed Web of Science ®Google Scholar
• Bedard PL, Tabernero J, Janku F, et al. A phase Ib dose-escalation study of the oral pan-PI3K inhibitor buparlisib (BKM120) in combination with the oral MEK1/2 inhibitor trametinib (GSK1120212) in patients with selected advanced solid tumors. Clin Cancer Res. 2015 Feb 15;21(4):730–738.
   PubMed Web of Science ®Google Scholar
• Becerra C, Infante JR, Garbo LE, et al. A five-arm, open-label, phase I/lb study to assess safety and tolerability of the oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with chemotherapy or erlotinib in patients with advanced solid tumors. Am Soc Clin Oncol. 2012;30(15_suppl): 3023–3023.
   Google Scholar
• Gandara DR, Leighl N, Delord JP, et al. A phase 1/1b study evaluating trametinib plus docetaxel or pemetrexed in patients with advanced non-small cell lung cancer. J Thorac Oncol. 2017 Mar;12(3):556–566.
   PubMed Web of Science ®Google Scholar
• Hoeflich KP, Merchant M, Orr C, et al. Intermittent administration of MEK inhibitor GDC-0973 plus PI3K inhibitor GDC-0941 triggers robust apoptosis and tumor growth inhibition. Cancer Res. 2012 Jan 01;72(1):210–219.
   PubMed Web of Science ®Google Scholar
• Rosen LS, LoRusso P, Ma WW, et al. A first-in-human phase I study to evaluate the MEK1/2 inhibitor, cobimetinib, administered daily in patients with advanced solid tumors. Invest New Drugs. 2016 Oct;34(5):604–613.
   PubMed Web of Science ®Google Scholar
• Larkin J, Ascierto PA, Dreno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014 Nov 13;371(20):1867–1876.
   PubMed Web of Science ®Google Scholar
• Ascierto PA, McArthur GA, Dreno B, et al. Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. 2016 Sep;17(9):1248–1260.
   PubMed Web of Science ®Google Scholar
• Shapiro G, LoRusso P, Kwak EL, et al. Clinical combination of the MEK inhibitor GDC-0973 and the PI3K inhibitor GDC-0941: a first-in-human phase Ib study testing daily and intermittent dosing schedules in patients with advanced solid tumors. J Clin Oncol. 2011;29(15_suppl):3005.
   Google Scholar
• Lieu CH, Hidalgo M, Berlin JD, et al. A phase Ib dose-escalation study of the safety, tolerability, and pharmacokinetics of cobimetinib and duligotuzumab in patients with previously treated locally advanced or metastatic cancers with mutant KRAS. Oncologist. 2017 Jun 07;22:1024–e89.
   PubMed Web of Science ®Google Scholar
• Lee PA, Wallace E, Marlow A, et al. Abstract 2515: preclinical development of ARRY-162, a potent and selective MEK 1/2 inhibitor. Cancer Res. 2014 Nov 17 12:39:11;70:2515.
   Google Scholar
• Watanabe K, Otsu S, Hirashima Y, et al. A phase I study of binimetinib (MEK162) in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol. 2016 Jun;77(6):1157–1164.
   PubMed Web of Science ®Google Scholar
• Bendell JC, Javle M, Bekaii-Saab TS, et al. A phase 1 dose-escalation and expansion study of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor. Br J Cancer. 2017 Feb 28;116(5):575–583.
   PubMed Web of Science ®Google Scholar
• Sullivan RJ, Weber JS, Patel SP, et al. A phase Ib/II study of BRAF inhibitor (BRAFi) encorafenib (ENCO) plus MEK inhibitor (MEKi) binimetinib (BINI) in cutaneous melanoma patients naive to BRAFi treatment. J Clin Oncol. 2015;33(15_suppl):9007.
   Web of Science ®Google Scholar
• Dummer R, Ascierto PA, Gogas HJ, et al. Results of COLUMBUS part 1: a phase III trial of encorafenib (ENCO) plus binimetinib (BINI) versus vemurafenib (VEM) or ENCO in BRAF-mutant melanoma. Society for Melanoma Research Thirteenth International Congress. Boston, USA MA 2016.
   Google Scholar
• Sebolt-Leopold JS, Merriman R, Omer C, et al. The biological profile of PD 0325901: a second generation analog of CI-1040 with improved pharmaceutical potential. Cancer Res. 2014 Oct 23 11:54:48;64:925.
   Google Scholar
• Kramer BW, Gotz R, Rapp UR. Use of mitogenic cascade blockers for treatment of C-Raf induced lung adenoma in vivo: CI-1040 strongly reduces growth and improves lung structure. BMC Cancer. 2004 Jun 01;4:24.
   PubMed Web of Science ®Google Scholar
• Lorusso PM, Adjei AA, Varterasian M, et al. Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. J Clin Oncol. 2005 Aug 10;23(23):5281–5293.
   PubMed Web of Science ®Google Scholar
• Rinehart J, Adjei AA, Lorusso PM, et al. Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer. J Clin Oncol. 2004 Nov 15;22(22):4456–4462.
   PubMed Web of Science ®Google Scholar
• LoRusso PM, Krishnamurthi SS, Rinehart JJ, et al. Phase I pharmacokinetic and pharmacodynamic study of the oral MAPK/ERK kinase inhibitor PD-0325901 in patients with advanced cancers. Clin Cancer Res. 2010 Mar 15;16(6):1924–1937.
   PubMed Web of Science ®Google Scholar
• Haura EB, Ricart AD, Larson TG, et al. A phase II study of PD-0325901, an oral MEK inhibitor, in previously treated patients with advanced non-small cell lung cancer. Clin Cancer Res. 2010 Apr 15;16(8):2450–2457.
   PubMed Web of Science ®Google Scholar
• Isshiki Y, Kohchi Y, Iikura H, et al. Design and synthesis of novel allosteric MEK inhibitor CH4987655 as an orally available anticancer agent. Bioorg Med Chem Lett. 2011;21(6):1795–1801.
   PubMed Web of Science ®Google Scholar
• Leijen S, Middleton MR, Tresca P, et al. Phase I dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of the MEK inhibitor RO4987655 (CH4987655) in patients with advanced solid tumors. Clin Cancer Res. 2012 Sep 01;18(17):4794–4805.
   PubMed Web of Science ®Google Scholar
• Zimmer L, Barlesi F, Martinez-Garcia M, et al. Phase I expansion and pharmacodynamic study of the oral MEK inhibitor RO4987655 (CH4987655) in selected patients with advanced cancer with RAS-RAF mutations. Clin Cancer Res. 2014 Aug 15;20(16):4251–4261.
   PubMed Web of Science ®Google Scholar
• Nakamichi S, Nokihara H, Yamamoto N, et al. Phase I and pharmacokinetics/pharmacodynamics study of the MEK inhibitor RO4987655 in Japanese patients with advanced solid tumors. Invest New Drugs. 2015 Jun;33(3):641–651.
   PubMed Web of Science ®Google Scholar
• Martinelli E, Troiani T, D’Aiuto E, et al. Antitumor activity of pimasertib, a selective MEK 1/2 inhibitor, in combination with PI3K/mTOR inhibitors or with multi-targeted kinase inhibitors in pimasertib-resistant human lung and colorectal cancer cells. Int J Cancer. 2013 Nov;133(9):2089–2101.
   PubMed Web of Science ®Google Scholar
• Awada A, Delord J, Houede N, et al. 604 Safety and recommended phase II dose (RP2D) of the selective oral MEK1/2 inhibitor pimasertib (MSC1936369B/AS703026): results of a phase I trial. Eur J Cancer. 2012;48:185–186.
   Web of Science ®Google Scholar
• Mahadevan D, Mita M, Richards D, et al. Phase I single dose, two-period and two-sequence cross-over trial to evaluate the relative bioavailability of two oral pimasertib formulations in advanced cancer patients. Cancer Chemother Pharmacol. 2017 Apr;79(4):681–688.
   PubMed Web of Science ®Google Scholar
• Wallace E, Lyssikatos J, Blake J, et al. Abstract #3696: AZD8330 (ARRY-424704): preclinical evaluation of a potent, selective MEK 1/2 inhibitor currently in phase I trials. Cancer Res. 2014 Oct 08 12:31:50;69:3696.
   Google Scholar
• Cohen RB, Aamdal S, Nyakas M, et al. A phase I dose-finding, safety and tolerability study of AZD8330 in patients with advanced malignancies. Eur J Cancer. 2013 May;49(7):1521–1529.
   PubMed Web of Science ®Google Scholar
• Iverson C, Larson G, Lai C, et al. RDEA119/BAY 869766: a potent, selective, allosteric inhibitor of MEK1/2 for the treatment of cancer. Cancer Res. 2009 Aug 31; 21:07:32;69:6839–6847.
   PubMed Web of Science ®Google Scholar
• Adjei AA, Richards DA, El-Khoueiry A, et al. A phase I study of the safety, pharmacokinetics, and pharmacodynamics of combination therapy with refametinib plus sorafenib in patients with advanced cancer. Clin Cancer Res. 2016 May 15;22(10):2368–2376.
   PubMed Web of Science ®Google Scholar
• Dong Q, Dougan DR, Gong X, et al. Discovery of TAK-733, a potent and selective MEK allosteric site inhibitor for the treatment of cancer. Bioorg Med Chem Lett. 2011;21(5):1315–1319.
   PubMed Web of Science ®Google Scholar
• Adjei AA, LoRusso P, Ribas A, et al. A phase I dose-escalation study of TAK-733, an investigational oral MEK inhibitor, in patients with advanced solid tumors. Invest New Drugs. 2017 Feb;35(1):47–58.
   PubMed Web of Science ®Google Scholar
• Haagensen EJ, Thomas HD, Schmalix WA, et al. Enhanced anti-tumour activity of the combination of the novel MEK inhibitor WX-554 and the novel PI3K inhibitor WX-037. Cancer Chemother Pharmacol. 2016 Dec;78(6):1269–1281.
   PubMed Web of Science ®Google Scholar
• Jamieson D, Griffin MJ, Sludden J, et al. A phase I pharmacokinetic and pharmacodynamic study of the oral mitogen-activated protein kinase kinase (MEK) inhibitor, WX-554, in patients with advanced solid tumours. Eur J Cancer. 2016;68:1–10.
   PubMed Web of Science ®Google Scholar
• Emery CM, Monaco K-A, Wang P, et al. BRAF-inhibitor associated MEK mutations increase RAF-dependent and-independent enzymatic activity. Mol Cancer Res. 2017 Jun 27 06:31:57;15:1431–1444.
   PubMed Web of Science ®Google Scholar
• Long GV, Fung C, Menzies AM, et al. Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma. Nat Commun. 2014;5:5694.
   PubMed Web of Science ®Google Scholar
• Breunig C, Mueller BJ, Umansky L, et al. BRaf and MEK inhibitors differentially regulate cell fate and microenvironment in human hepatocellular carcinoma. Clin Cancer Res. 2014 May 01;20(9):2410–2423.
   PubMed Web of Science ®Google Scholar
• Grimaldi A, Zarone MR, Irace C, et al. Non-coding RNAs as a new dawn in tumor diagnosis. Semin Cell Dev Biol. 2017 Jul 29.
   PubMedGoogle Scholar
• Chen Y, Li C, Pan Y, et al. The emerging role and promise of long noncoding RNAs in lung cancer treatment. Cell Physiol Biochem. 2016;38(6):2194–2206.
   PubMed Web of Science ®Google Scholar
• Ammad-Ud-Din M, Khan SA, Malani D, et al. Drug response prediction by inferring pathway-response associations with kernelized Bayesian matrix factorization. Bioinformatics. 2016 Sep 01;32(17):i455–i63.
   PubMed Web of Science ®Google Scholar
• Hatzivassiliou G, Haling JR, Chen H, et al. Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers. Nature. 2013 Sep 12;501(7466):232–236.
   PubMed Web of Science ®Google Scholar
• Yoon YK, Kim HP, Han SW, et al. KRAS mutant lung cancer cells are differentially responsive to MEK inhibitor due to AKT or STAT3 activation: implication for combinatorial approach. Mol Carcinog. 2010 Apr;49(4):353–362.
   PubMed Web of Science ®Google Scholar
• Meng J, Dai B, Fang B, et al. Combination treatment with MEK and AKT inhibitors is more effective than each drug alone in human non-small cell lung cancer in vitro and in vivo. PLoS One. 2010 Nov 29;5(11):e14124.
   PubMed Web of Science ®Google Scholar
• Papadimitrakopoulou V, Lee JJ, Wistuba II, et al. The BATTLE-2 study: a biomarker-integrated targeted therapy study in previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol. 2016 Aug 01.
   PubMed Web of Science ®Google Scholar
• Ciuffreda L, Del Curatolo A, Falcone I, et al. Lack of growth inhibitory synergism with combined MAPK/PI3K inhibition in preclinical models of pancreatic cancer. Ann Oncology. 2017 Nov 01;28(11):2896–2898.
   PubMed Web of Science ®Google Scholar
• Milella M, Falcone I, Conciatori F, et al. PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer. Sci Rep. 2017 Feb;21(7):43013.
   Google Scholar
• Ross JS, Wang K, Chmielecki J, et al. The distribution of BRAF gene fusions in solid tumors and response to targeted therapy. Int J Cancer. 2016 Feb 15;138(4):881–890.
   PubMed Web of Science ®Google Scholar
• Jang JS, Lee A, Li J, et al. Common oncogene mutations and novel SND1-BRAF transcript fusion in lung adenocarcinoma from never smokers. Sci Rep. 2015 May 18;5:9755.
   PubMed Web of Science ®Google Scholar
• Nakaoku T, Tsuta K, Ichikawa H, et al. Druggable oncogene fusions in invasive mucinous lung adenocarcinoma. Clin Cancer Res. 2014 Jun 15;20(12):3087–3093.
   PubMed Web of Science ®Google Scholar
• Lee JW, Zhang Y, Park HS, et al. Abstract 2334: anti-cancer efficacy of the combination with immunomodulatory antibodies and MEK inhibitor for KRAS mutation and p53 knockout driven lung cancer. Cancer Res. 2016 Jul 22;76:2334. 11:37:04.
   Web of Science ®Google Scholar
• Liu L, Mayes PA, Eastman S, et al. The BRAF and MEK inhibitors dabrafenib and trametinib: effects on immune function and in combination with immunomodulatory antibodies targeting PD-1, PD-L1, and CTLA-4. Clin Cancer Res 2015 Mar 11; 07:08:43;21(7):1639–1651.
   Web of Science ®Google Scholar
• Ebert PJR, Cheung J, Yang Y, et al. MAP kinase inhibition promotes T cell and anti-tumor activity in combination with PD-L1 checkpoint blockade. Immunity. 2016 Mar 15;44(3):609–621.
   PubMed Web of Science ®Google Scholar
• Ribas A, Butler M, Lutzky J, et al. Phase I study combining anti-PD-L1 (MEDI4736) with BRAF (dabrafenib) and/or MEK (trametinib) inhibitors in advanced melanoma. J Clin Oncol. 2015;33(15_suppl):3003.
   Web of Science ®Google Scholar
• Bendell JC, Kim TW, Goh BC, et al. Clinical activity and safety of cobimetinib (COBI) and atezolizumab in colorectal cancer (CRC). Am Soc Clin Oncol. 2016;34 (15_suppl): 3502–3502.
   Google Scholar
• Hwu P, Hamid O, Gonzalez R, et al. Preliminary safety and clinical activity of atezolizumab combined with cobimetinib and vemurafenib in BRAF V600-mutant metastatic melanoma. Eur Soc Med Oncol. 2016;27.
   Google Scholar