We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×

The RAF-MEK-ERK pathway: targeting ERK to overcome obstacles to effective cancer therapy

    Zutao Yu

    Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Central South University, 410013, Changsha, Hunan, China

    ,
    Shiqi Ye

    School of Medicine, Shenzhen University, 518060, Shenzhen, Guangdong, China

    ,
    Gaoyun Hu

    Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Central South University, 410013, Changsha, Hunan, China

    ,
    Meng Lv

    Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Central South University, 410013, Changsha, Hunan, China

    ,
    Zhijun Tu

    Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Central South University, 410013, Changsha, Hunan, China

    ,
    Kun Zhou

    Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Central South University, 410013, Changsha, Hunan, China

    &
    Qianbin Li

    *Author for correspondence:

    E-mail Address: qbli@csu.edu.cn

    Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Central South University, 410013, Changsha, Hunan, China

    Published Online:https://doi.org/10.4155/fmc.14.143

    Aim: Currently, dozens of BRAF inhibitors and MEK inhibitors targeting RAF-MEK-ERK pathway have been introduced into clinical trials for cancer therapy. However, after 6–8 months of initial response, acquired drug resistance among the majority of those treated patients sharply diminished their clinical efficacy. Discussion: Important mechanisms responsible for acquired resistance of BRAF inhibitors and MEK inhibitors have been elucidated. Continually, ERK1/2 locates in the critical position and features unique characteristics, such as activating hundreds of substrates, participating in feedback regulation, being catalyzed by MEK specifically and no acquired resistant mutation. Conclusion: Taking in account the inspiring outcomes of ERK inhibitors in preclinical research, ERK1/2 might be the optimal target to overcome acquired drug resistance in RAF-MEK-ERK pathway.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1 Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics 2014. CA. Cancer J. Clin. 64(1), 9–29 (2014).
    • 2 Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 100(1), 57–70 (2000).
    • 3 Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 144(5), 646–674 (2011).•• Excellent review of the hallmarks of tumorigenesis and provide the macroscopic outline of cancer.
    • 4 Dhillon AS, Hagan S, Rath O, Kolch W. MAP kinase signalling pathways in cancer. Oncogene 26(22), 3279–3290 (2007).
    • 5 Yang SH, Sharrocks AD, Whitmarsh AJ. MAP kinase signalling cascades and transcriptional regulation. Gene 513(1), 1–13 (2013).
    • 6 Meister M, Tomasovic A, Banning A, Tikkanen R. Mitogen-activated protein (MAP) kinase scaffolding proteins: a recount. Int. J. Mol. Sci. 14(3), 4854–4884 (2013).
    • 7 Kyriakis JM, Avruch J. Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update. Physiol. Rev. 92(2), 689–737 (2012).
    • 8 Jones DTW, Gronych J, Lichter P, Witt O, Pfister SM. MAPK pathway activation in pilocytic astrocytoma. Cell. Mol. Life Sci. 69(11), 1799–1811 (2012).
    • 9 Lowenstein EJ, Daly RJ, Batzer AG et al. The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling. Cell 70(3), 431–442 (1992).
    • 10 Chin L, Tam A, Pomerantz J et al. Essential role for oncogenic Ras in tumour maintenance. Nature 400(6743), 468–472 (1999).
    • 11 Van Aelst L, Barr M, Marcus S, Polverino A, Wigler M. Complex formation between RAS and RAF and other protein kinases. Proc. Natl Acad. Sci. USA 90(13), 6213–6217 (1993).
    • 12 Yoon S, Seger R. The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions. Growth Factors 24(1), 21–44 (2006).
    • 13 Mackesy DZ, Goalstone ML. ERK5: novel mediator of insulin and TNF‐stimulated VCAM‐1 expression in vascular cells. J. Diabetes 6(6), 595–602 (2014).
    • 14 Zhou Y, Tanaka T, Sugiyama N et al. p38-Mediated phosphorylation of Eps15 endocytic adaptor protein. FEBS Lett. 588(1), 131–137 (2014).
    • 15 Sanchez-Fernandez G, Cabezudo S, Garcia-Hoz C, Tobin AB, Mayor F Jr, Ribas C. ERK5 activation by Gq-coupled muscarinic receptors is independent of receptor internalization and beta-arrestin recruitment. PLoS One 8(12), e84174 (2013).
    • 16 Zhang T, Inesta-Vaquera F, Niepel M et al. Discovery of potent and selective covalent inhibitors of JNK. Chem. Biol. 19(1), 140–154 (2012).
    • 17 Osborne JK, Zaganjor E, Cobb MH. Signal control through Raf: in sickness and in health. Cell Res. 22(1), 14–22 (2012).
    • 18 Shugar D, Fabbro D. Inhibitors of protein kinases. Biochim. Biophys. Acta 1834(7), 1269–1270 (2013).
    • 19 Neuzillet C, Tijeras-Raballand A, De Mestier L, Cros J, Faivre S, Raymond E. MEK in cancer and cancer therapy. Pharmacol. Ther. 141(2), 160–171 (2014).
    • 20 Taketomi A, Shirabe K, Muto J et al. A rare point mutation in the Ras oncogene in hepatocellular carcinoma. Surg. Today 43(3), 289–292 (2013).
    • 21 Bos JL. Ras oncogenes in human cancer: a review. Cancer Res. 49(17), 4682–4689 (1989).
    • 22 Grabocka E, Pylayeva-Gupta Y, Jones MJ et al. Wild-Type H-and N-Ras promote mutant K-Ras-driven tumorigenesis by modulating the DNA damage response. Cancer Cell 25(2), 243–256 (2014).
    • 23 Huang TG, Karsy M, Zhuge J, Zhong MH, Liu DL. B-Raf and the inhibitors: from bench to bedside. J. Hematol. Oncol. 6(1), 30 (2013).• Important paper elucidate the drug resistance of BRAF inhibitors.
    • 24 Rahman MA, Salajegheh A, Smith RA, Lam AK. B-Raf mutation: a key player in molecular biology of cancer. Exp. Mol. Pathol. 95(3), 336–342 (2013).
    • 25 Hatzivassiliou G, Song K, Yen I et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 464(7287), 431–435 (2010).
    • 26 Guo W, Hao B, Wang Q, Lu Y, Yue J. Requirement of B-Raf, C-Raf, and A-Raf for the growth and survival of mouse embryonic stem cells. Exp. Cell Res. 319(18), 2801–2811 (2013).
    • 27 Buonato JM, Lazzara MJ. ERK1/2 blockade prevents epithelial-mesenchymal transition in lung cancer cells and promotes their sensitivity to EGFR inhibition. Cancer Res. 74(1), 309–319 (2014).
    • 28 Stuart DD, Sellers WR. Targeting RAF-MEK-ERK kinase-scaffold interactions in cancer. Nat. Med. 19(5), 538–540 (2013).
    • 29 Kim KB, Kefford R, Pavlick AC et al. Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. J. Clin. Oncol. 31(4), 482–489 (2013).
    • 30 Sievert AJ, Lang SS, Boucher KL et al. Paradoxical activation and RAF inhibitor resistance of BRAF protein kinase fusions characterizing pediatric astrocytomas. Proc. Natl Acad. Sci. USA 110(15), 5957–5962 (2013).
    • 31 Villanueva J, Infante JR, Krepler C et al. Concurrent MEK2 mutation and BRAF amplification confer resistance to BRAF and MEK inhibitors in melanoma. Cell Rep. 4(6), 1090–1099 (2013).
    • 32 Solit DB, Rosen N. Resistance to BRAF inhibition in melanomas. N. Engl. J. Med. 364(8), 772–774 (2011).
    • 33 Flaherty KT, Puzanov I, Kim KB et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 363(9), 809–819 (2010).
    • 34 Morris EJ, Jha S, Restaino CR et al. Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors. Cancer Discov. 3(7), 742–750 (2013).• Key paper report biological efficay of novel ERK inhibitors, and especially shown that ERK inhibitors could overcome acquired resistance of up-stream inhibitors.
    • 35 Nissan MH, Rosen N, Solit DB. ERK pathway inhibitors: how low should we go? Cancer Discov. 3(7), 719–721 (2013).
    • 36 Hatzivassiliou G, Liu B, O'brien C et al. ERK inhibition overcomes acquired resistance to MEK inhibitors. Mol. Cancer Ther. 11(5), 1143–1154 (2012).
    • 37 Roskoski Jr R. ERK1/2 MAP kinases: structure, function, and regulation. Pharmacol. Res. 66(2), 105–143 (2012).
    • 38 Luke JJ, Hodi FS. Ipilimumab, vemurafenib, dabrafenib, and trametinib: synergistic competitors in the clinical management of BRAF mutant malignant melanoma. Oncologist 18(6), 717–725 (2013).
    • 39 Van Allen EM, Wagle N, Sucker A et al. The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov. 4(1), 94–109 (2014).
    • 40 Bolick SCE, Landowski TH, Boulware D et al. The farnesyl transferase inhibitor, FTI-277, inhibits growth and induces apoptosis in drug-resistant myeloma tumor cells. Leukemia 17(2), 451–457 (2003).
    • 41 Kloog Y, Cox AD. RAS inhibitors: potential for cancer therapeutics. Mol. Med. Today 6(10), 398–402 (2000).
    • 42 Blum R, Elkon R, Yaari S et al. Gene expression signature of human cancer cell lines treated with the Ras inhibitor Salirasib (S-Farnesylthiosalicylic Acid). Cancer Res. 67(7), 3320–3328 (2007).
    • 43 Mark GE, Rapp UR. Primary structure of v-raf: relatedness to the src family of oncogenes. Science 224(4646), 285–289 (1984).
    • 44 Davies H, Bignell GR, Cox C et al. Mutations of the BRAF gene in human cancer. Nature 417(6892), 949–954 (2002).
    • 45 Hauschild A, Agarwala SS, Trefzer U et al. Results of a Phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable Stage III or Stage IV melanoma. J. Clin. Oncol. 27(17), 2823–2830 (2009).
    • 46 Kudo M, Ueshima K. Positioning of a molecular-targeted agent, sorafenib, in the treatment algorithm for hepatocellular carcinoma and implication of many complete remission cases in Japan. Oncology 78(Suppl.1), 154–166 (2010).
    • 47 Joseph EW, Pratilas CA, Poulikakos PI et al. The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner. Proc. Natl Acad. Sci. USA 107(33), 14903–14908 (2010).
    • 48 Chapman PB, Hauschild A, Robert C et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 364(26), 2507–2516 (2011).
    • 49 Ott PA, Henry T, Baranda SJ et al. Inhibition of both BRAF and MEK in BRAF(V600E) mutant melanoma restores compromised dendritic cell (DC) function while having differential direct effects on DC properties. Cancer Immunol. Immunother. 62(4), 811–822 (2013).
    • 50 Trunzer K, Pavlick AC, Schuchter L et al. Pharmacodynamic effects and mechanisms of resistance to vemurafenib in patients with metastatic melanoma. J. Clin. Oncol. 31(14), 1767–1774 (2013).
    • 51 Wagle N, Emery C, Berger MF et al. Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. J. Clin. Oncol. 29(22), 3085–3096 (2011).
    • 52 Falchook GS, Long GV, Kurzrock R et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a Phase 1 dose-escalation trial. Lancet 379(9829), 1893–1901 (2012).
    • 53 Long GV, Trefzer U, Davies MA et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol. 13(11), 1087–1095 (2012).
    • 54 Hauschild A, Grob JJ, Demidov LV et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 380(9839), 358–365 (2012).
    • 55 Garcia-Gomez A, Ocio EM, Pandiella A, San Miguel JF, Garayoa M. RAF265, a dual BRAF and VEGFR2 inhibitor, prevents osteoclast formation and resorption. Therapeutic implications. Invest. New Drugs 31(1), 200–205 (2013).
    • 56 Hoeflich KP, Herter S, Tien J et al. Antitumor efficacy of the novel RAF inhibitor GDC-0879 is predicted by BRAFV600E mutational status and sustained extracellular signal-regulated kinase/mitogen-activated protein kinase pathway suppression. Cancer Res. 69(7), 3042–3051 (2009).
    • 57 Garber K. Melanoma combination therapies ward off tumor resistance. Nat. Biotechnol. 31(8), 666–668 (2013).
    • 58 Roskoski Jr R. MEK1/2 dual-specificity protein kinases: structure and regulation. Biochem. Biophys. Res. Commun. 417(1), 5–10 (2012).
    • 59 Wagle N, Van Allen EM, Treacy DJ et al. MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired resistance to combined RAF/MEK inhibition. Cancer Discov. 4(1), 61–68 (2014).
    • 60 Wallace EM, Lyssikatos JP, Yeh T, Winkler JD, Koch K. Progress towards therapeutic small molecule MEK inhibitors for use in cancer therapy. Curr. Top. Med. Chem. 5(2), 215–229 (2005).
    • 61 Martin-Liberal J, Lagares-Tena L, Larkin J. Prospects for MEK inhibitors for treating cancer. Expert Opin. Drug Saf. 13(4), 483–495 (2014).•• Important review outline the future research and application of MEK inhibitors.
    • 62 Ge X, Fu Y, Meadows GG. U0126, a mitogen-activated protein kinase kinase inhibitor, inhibits the invasion of human A375 melanoma cells. Cancer Lett. 179(2), 133–140 (2002).
    • 63 Mccubrey JA, Steelman LS, Abrams SL et al. Emerging MEK inhibitors. Expert Opin. Emerg. Drugs 15(2), 203–223 (2010).
    • 64 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. 22(22), 4456–4462 (2004).
    • 65 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. 16(6), 1924–1937 (2010).
    • 66 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. 16(8), 2450–2457 (2010).
    • 67 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 133(9), 2089–2101 (2013).
    • 68 Wong H, Vernillet L, Peterson A et al. Bridging the gap between preclinical and clinical studies using pharmacokinetic–pharmacodynamic modeling: an analysis of GDC-0973, a MEK inhibitor. Clin. Cancer Res. 18(11), 3090–3099 (2012).
    • 69 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. 17(5), 989–1000 (2011).
    • 70 Yamaguchi T, Kakefuda R, Tajima N, Sowa Y, Sakai T. Antitumor activities of JTP-74057 (GSK1120212), a novel MEK1/2 inhibitor, on colorectal cancer cell lines in vitro and in vivo. Int. J. Oncol. 39(1), 23–31 (2011).
    • 71 Infante JR, Fecher LA, Falchook GS et al. Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol. 13(8), 773–781 (2012).
    • 72 Flaherty KT, Robert C, Hersey P et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N. Engl. J. Med. 367(2), 107–114 (2012).
    • 73 Wallace EM, Lyssikatos J, Blake JF et al. Potent and selective mitogen-activated protein kinase kinase (MEK) 1,2 inhibitors. 1. 4-(4-bromo-2-fluorophenylamino)-1- methylpyridin-2(1H)-ones. J. Med. Chem. 49(2), 441–444 (2006).
    • 74 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. 6(8), 2209–2219 (2007).
    • 75 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. 13(5), 1576–1583 (2007).
    • 76 Little AS, Balmanno K, Sale MJ et al. Amplification of the driving oncogene, KRAS or BRAF, underpins acquired resistance to MEK1/2 inhibitors in colorectal cancer cells. Sci. Signal 4(166), ra17 (2011).
    • 77 Bid HK, Kibler A, Phelps DA et al. Development, characterization, and reversal of acquired resistance to the MEK1 inhibitor Selumetinib (AZD6244) in an in vivo model of childhood Astrocytoma. Clin. Cancer Res. 19(24), 6716–6729 (2013).
    • 78 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. 26(13), 2139–2146 (2008).
    • 79 Bennouna J, Lang I, Valladares-Ayerbes M et al. A Phase II, open-label, randomised study to assess the efficacy and safety of the MEK1/2 inhibitor AZD6244 (ARRY-142886) versus capecitabine monotherapy in patients with colorectal cancer who have failed one or two prior chemotherapeutic regimens. Invest. New Drugs 29(5), 1021–1028 (2011).
    • 80 Bodoky G, Timcheva C, Spigel DR et al. A Phase II open-label randomized study to assess the efficacy and safety of selumetinib (AZD6244 [ARRY-142886]) versus capecitabine in patients with advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy. Invest. New Drugs 30(3), 1216–1223 (2012).
    • 81 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. 5(10), 1630–1636 (2010).
    • 82 Kirkwood JM, Bastholt L, Robert C et al. Phase II, open-label, randomized trial of the MEK1/2 inhibitor selumetinib as monotherapy versus temozolomide in patients with advanced melanoma. Clin. Cancer Res. 18(2), 555–567 (2012).
    • 83 O'neil BH, Goff LW, Kauh JS et al. Phase II study of the mitogen-activated protein kinase 1/2 inhibitor selumetinib in patients with advanced hepatocellular carcinoma. J. Clin. Oncol. 29(17), 2350–2356 (2011).
    • 84 Kalia M. Personalized oncology: recent advances and future challenges. Metabolism 62(Suppl.1), s11–s14 (2013).
    • 85 Sullivan RJ, Flaherty KT. Resistance to BRAF-targeted therapy in melanoma. Eur. J. Cancer 49(6), 1297–1304 (2013).
    • 86 Sos ML, Levin RS, Gordan JD et al. Oncogene mimicry as a mechanism of primary resistance to BRAF Inhibitors. Cell Rep. 8(4), 1037–1048 (2014).
    • 87 Sheppard KE, Cullinane C, Hannan KM et al. Synergistic inhibition of ovarian cancer cell growth by combining selective PI3K/mTOR and RAS/ERK pathway inhibitors. Eur. J. Cancer 49(18), 3936–3944 (2013).
    • 88 Balmanno K, Cook SJ. Tumour cell survival signalling by the ERK1/2 pathway. Cell Death Differ. 16(3), 368–377 (2009).
    • 89 Balmanno K, Chell SD, Gillings AS, Hayat S, Cook SJ. Intrinsic resistance to the MEK1/2 inhibitor AZD6244 (ARRY-142886) is associated with weak ERK1/2 signalling and/or strong PI3K signalling in colorectal cancer cell lines. Int. J. Cancer 125(10), 2332–2341 (2009).
    • 90 Lui VW, Hedberg ML, Li H et al. Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers. Cancer Discov. 3(7), 761–769 (2013).
    • 91 Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 464(7287), 427–430 (2010).
    • 92 Basile KJ, Abel EV, Dadpey N, Hartsough EJ, Fortina P, Aplin AE. In vivo MAPK reporting reveals the heterogeneity in tumoral selection of resistance to RAF inhibitors. Cancer Res. 73(23), 7101–7110 (2013).
    • 93 Nazarian R, Shi H, Wang Q et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468(7326), 973–977 (2010).
    • 94 Carlino MS, Todd JR, Gowrishankar K et al. Differential activity of MEK and ERK inhibitors in BRAF inhibitor resistant melanoma. Mol. Oncol. 8(3), 544–554 (2014).
    • 95 Poulikakos PI, Persaud Y, Janakiraman M et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 480(7377), 387–390 (2011).
    • 96 Antony R, Emery CM, Sawyer AM, Garraway LA. C-RAF mutations confer resistance to RAF inhibitors. Cancer Res. 73(15), 4840–4851 (2013).
    • 97 Emery CM, Vijayendran KG, Zipser MC et al. MEK1 mutations confer resistance to MEK and B-RAF inhibition. Proc. Natl Acad. Sci. USA 106(48), 20411–20416 (2009).
    • 98 Wang H, Daouti S, Li WH et al. Identification of the MEK1(F129L) activating mutation as a potential mechanism of acquired resistance to MEK inhibition in human cancers carrying the B-RafV600E mutation. Cancer Res. 71(16), 5535–5545 (2011).
    • 99 Fritsche-Guenther R, Witzel F, Sieber A et al. Strong negative feedback from Erk to Raf confers robustness to MAPK signalling. Mol. Syst. Biol. 7, 489 (2011).
    • 100 Shin SY, Rath O, Choo SM et al. Positive- and negative-feedback regulations coordinate the dynamic behavior of the Ras-Raf-MEK-ERK signal transduction pathway. J. Cell Sci. 122(3), 425–435 (2009).
    • 101 Ritt DA, Monson DM, Specht SI, Morrison DK. Impact of feedback phosphorylation and Raf heterodimerization on normal and mutant B-Raf signaling. Mol. Cell Biol. 30(3), 806–819 (2010).
    • 102 Margarit SM, Sondermann H, Hall BE et al. Structural evidence for feedback activation by Ras. GTP of the Ras-specific nucleotide exchange factor SOS. Cell 112(5), 685–695 (2003).
    • 103 Huang CY, Tan TH. DUSPs, to MAP kinases and beyond. Cell Biosci. 2(1), 24 (2012).
    • 104 Lito P, Pratilas CA, Joseph EW et al. Relief of profound feedback inhibition of mitogenic signaling by RAF inhibitors attenuates their activity in BRAFV600E melanomas. Cancer Cell 22(5), 668–682 (2012).
    • 105 Whittaker SR, Theurillat JP, Van Allen E et al. A genome-scale RNA interference screen implicates NF1 loss in resistance to RAF inhibition. Cancer Discov. 3(3), 350–362 (2013).
    • 106 Su F, Bradley WD, Wang Q et al. Resistance to selective BRAF inhibition can be mediated by modest upstream pathway activation. Cancer Res. 72(4), 969–978 (2012).
    • 107 Aronov AM, Tang Q, Martinez-Botella G et al. Structure-guided design of potent and selective pyrimidylpyrrole inhibitors of extracellular signal-regulated kinase (ERK) using conformational control. J. Med. Chem. 52(20), 6362–6368 (2009).
    • 108 Camp ER, Summy J, Bauer TW, Liu W, Gallick GE, Ellis LM. Molecular mechanisms of resistance to therapies targeting the epidermal growth factor receptor. Clin. Cancer Res. 11(1), 397–405 (2005).
    • 109 Turke AB, Zejnullahu K, Wu YL et al. Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell 17(1), 77–88 (2010).
    • 110 Johannessen CM, Boehm JS, Kim SY et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468(7326), 968–972 (2010).
    • 111 Shi H, Moriceau G, Kong X et al. Melanoma whole-exome sequencing identifies (V600E)B-RAF amplification-mediated acquired B-RAF inhibitor resistance. Nat. Commun. 3, 724 (2012).
    • 112 Poulikakos PI, Solit DB. Resistance to MEK inhibitors: should we co-target upstream? Sci. Signal 4(166), pe16 (2011).
    • 113 Robbins DJ, Zhen E, Owaki H et al. Regulation and properties of extracellular signal-regulated protein kinases 1 and 2 in vitro. J. Biol. Chem. 268(7), 5097–5106 (1993).
    • 114 Hancock CN, Macias A, Lee EK, Yu SY, Mackerell AD Jr, Shapiro P. Identification of novel extracellular signal-regulated kinase docking domain inhibitors. J. Med. Chem. 48(14), 4586–4595 (2005).
    • 115 Sulzmaier FJ, Ramos JW. RSK isoforms in cancer cell invasion and metastasis. Cancer Res. 73(20), 6099–6105 (2013).
    • 116 Jameson KL, Mazur PK, Zehnder AM et al. IQGAP1 scaffold-kinase interaction blockade selectively targets RAS-MAP kinase-driven tumors. Nat. Med. 19(5), 626–630 (2013).
    • 117 Lefloch R, Pouyssegur J, Lenormand P. Single and combined silencing of ERK1 and ERK2 reveals their positive contribution to growth signaling depending on their expression levels. Mol. Cell Biol. 28(1), 511–527 (2008).
    • 118 Huang C, Jacobson K, Schaller MD. MAP kinases and cell migration. J. Cell Sci. 117(20), 4619–4628 (2004).
    • 119 Vanhook AM. Proliferation or differentiation depends on ERK localization. 7(333), doi:10.1126/scisignal.2005658 (2014) (Epub ahead of print).
    • 120 Radtke S, Milanovic M, Rosse C et al. ERK2 but not ERK1 mediates HGF-induced motility in non-small cell lung carcinoma cell lines. J. Cell Sci. 126(11), 2381–2391 (2013).
    • 121 Marchi M, D'antoni A, Formentini I et al. The N-terminal domain of ERK1 accounts for the functional differences with ERK2. PLoS One 3(12), e3873 (2008).
    • 122 Lefloch R, Pouyssegur J, Lenormand P. Total ERK1/2 activity regulates cell proliferation. Cell Cycle 8(5), 705–711 (2009).•• Important paper demonstrates the different function of ERK1 and ERK2.
    • 123 Guegan JP, Ezan F, Theret N, Langouet S, Baffet G. MAPK signaling in cisplatin-induced death: predominant role of ERK1 over ERK2 in human hepatocellular carcinoma cells. Carcinogenesis 34(1), 38–47 (2013).
    • 124 Shaul YD, Seger R. ERK1c regulates Golgi fragmentation during mitosis. J. Cell Biol. 172(6), 885–897 (2006).
    • 125 Cordero P, Ashley EA. Whole-genome sequencing in personalized therapeutics. Clin. Pharmacol. Ther. 91(6), 1001–1009 (2012).
    • 126 Fang W, Zhang J, Liang W et al. Efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors for Chinese patients with squamous cell carcinoma of lung harboring EGFR mutation. J. Thor. Dis. 5(5), 585–592 (2013).
    • 127 Qin J, Xin H, Nickoloff BJ. Specifically targeting ERK1 or ERK2 kills melanoma cells. J. Transl. Med. 10, 15 (2012).
    • 128 Gavrin LK, Saiah E. Approaches to discover non-ATP site kinase inhibitors. Med. Chem. Commun. 4(1), 41 (2013).•• Key paper elucidate the features of non-ATP inhibitors and how to design.
    • 129 Yap JL, Worlikar S, Mackerell AD Jr, Shapiro P, Fletcher S. Small-molecule inhibitors of the ERK signaling pathway: towards novel anticancer therapeutics. Chem. Med. Chem. 6(1), 38–48 (2011).
    • 130 Clydesdale GJ, Dandie GW, Muller HK. Ultraviolet light induced injury: immunological and inflammatory effects. Immunol. Cell Biol. 79(6), 547–568 (2001).
    • 131 Li J, Malakhova M, Mottamal M et al. Norathyriol suppresses skin cancers induced by solar ultraviolet radiation by targeting ERK kinases. Cancer Res. 72(1), 260–270 (2012).
    • 132 Bode AM, Dong Z. Mitogen-activated protein kinase activation in UV-induced signal transduction. Sci. STKE 2003(167), RE2 (2003).
    • 133 Ohori M, Kinoshita T, Okubo M et al. Identification of a selective ERK inhibitor and structural determination of the inhibitor-ERK2 complex. Biochem. Biophys. Res. Commun. 336(1), 357–363 (2005).
    • 134 Blake JF, Gaudino JJ, De Meese J et al. Discovery of 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine inhibitors of Erk2. Bioorg. Med. Chem. Lett. 24(12), 2635–2639 (2014).
    • 135 Gerlach MP, Seipelt I, Mueller G et al. Novel pyrido[2,3-b]pyrazines as orally active ERK inhibitors. Presented at: 242nd ACS National Meeting & Exposition, Denver, CO, United States, 28 August – 1 September 2011, pagesMEDI-243.
    • 136 Eralp Y, Derin D, Ozluk Y et al. MAPK overexpression is associated with anthracycline resistance and increased risk for recurrence in patients with triple-negative breast cancer. Ann. Oncol. 19(4), 669–674 (2008).
    • 137 The Broad Institute; Dana-Farber Cancer Institute: WO2013169858A1 (2013).
    • 138 Clinical Trials. www.ClinicalTrials.gov.
    • 139 Merck sharp & Dohme corp.: WO2013063214A1 (2013).
    • 140 Schering corp.: WO2012087772A1 (2012).
    • 141 Schering corp.: WO2012036997A1 (2012).
    • 142 Schering corp.: WO2012030685A2 (2012).
    • 143 Schering corp.: WO2012058127A2 (2012).
    • 144 Merck sharp & Dohme corp.; Schering corp.: WO2011163330A1 (2011).
    • 145 Schering corp.: WO2009105500A1 (2009).
    • 146 Schering corp.; Merck sharp & Dohme corp.: US20090118284A1 (2009).
    • 147 Nissan MH, Rosen N, Solit DB. ERK pathway inhibitors: how low should we go? Cancer Discov. 3(7), 719–721 (2013).
    • 148 Alderton GK. Therapy: combination and dosing schedule are key. Nat. Rev. Cancer 14(4), 215–215 (2014).
    • 149 Kiel C, Serrano L. Challenges ahead in signal transduction: MAPK as an example. Curr. Opin. Biotechnol. 23(3), 305–314 (2012).
    • 150 Cohen P, Alessi DR. Kinase drug discovery-what's next in the field? ACS Chem. Biol. 8(1), 96–104 (2013).