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Open Access 01-04-2014 | Original Article

Overexpression of MET is a new predictive marker for anti-EGFR therapy in metastatic colorectal cancer with wild-type KRAS

Authors: Tomokazu Kishiki, Hiroaki Ohnishi, Tadahiko Masaki, Kouki Ohtsuka, Yasuo Ohkura, Jyunji Furuse, Takashi Watanabe, Masanori Sugiyama

Published in: Cancer Chemotherapy and Pharmacology | Issue 4/2014

Abstract

Purpose

Since the KRAS mutation is not responsible for all metastatic colorectal cancer (mCRC) patients with resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibody (MoAb) therapy, new predictive and prognostic factors are actively being sought.

Methods

We retrospectively evaluated the efficacy of anti-EGFR MoAb-based therapies in 91 patients with mCRC according to KRAS, BRAF, and PIK3CA mutational status as well as PTEN and MET expression.

Results

In the patient group with wild-type KRAS, the presence of BRAF mutation or PIK3CA mutations was associated with lower disease control rate (DCR), shorter progression-free survival (PFS), and shorter overall survival. Patients with MET overexpression also showed lower DCR and shorter PFS when compared with patients with normal MET expression. In a separate analysis, 44 patients harboring wild-type KRAS tumors were sorted into subgroups of 25 patients without abnormality in three molecules (BRAF, PIK3CA and MET) and 19 patients with abnormality in at least one of these three molecules. The former group showed significantly higher DCR and longer PFS following anti-EGFR therapy than the latter group.

Conclusions

Our data point to the usefulness of MET overexpression, in addition to BRAF and PIK3CA mutations, as a new predictive marker for responsiveness to anti-EGFR MoAbs in mCRC patients with wild-type KRAS. This study also suggests that application of multiple biomarkers is more effective than the use of a single marker in selecting patients who might benefit from anti-EGFR therapy.

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Ciardiello F, Tortora G (2008) EGFR antagonists in cancer treatment. N Engl J Med 358(11):1160–1174PubMedCrossRef

Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A et al (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351(4):337–345PubMedCrossRef

Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, Zanon C, Moroni M, Veronese S et al (2007) Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res 67(6):2643–2648PubMedCrossRef

Saridaki Z, Tzardi M, Papadaki C, Sfakianaki M, Pega F, Kalikaki A et al (2011) Impact of KRAS, BRAF, PIK3CA mutations, PTEN, AREG, EREG expression and skin rash in ≥2 line cetuximab-based therapy of colorectal cancer patients. PLoS ONE 6(1):e15980PubMedCentralPubMedCrossRef

Di Fiore F, Blanchard F, Charbonnier F, Le Pessot F, Lamy A, Galais MP et al (2007) Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by cetuximab plus chemotherapy. Br J Cancer 96(8):1166–1169PubMedCentralPubMedCrossRef

Lievre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF et al (2006) KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 66(8):3992–3995PubMedCrossRef

De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G et al (2010) Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol 11(8):753–762PubMedCrossRef

Ulivi P, Capelli L, Valgiusti M, Zoli W, Scarpi E, Chiadini E et al (2012) Predictive role of multiple gene alterations in response to cetuximab in metastatic colorectal cancer: a single center study. J Transl Med 10:87PubMedCentralPubMedCrossRef

Bardelli A, Siena S (2010) Molecular mechanisms of resistance to cetuximab and panitumumab in colorectal cancer. J Clin Oncol 28(7):1254–1261PubMedCrossRef

10.

Sartore-Bianchi A, Martini M, Molinari F, Veronese S, Nichelatti M, Artale S et al (2009) PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res 69(5):1851–1857PubMedCrossRef

11.

Loupakis F, Pollina L, Stasi I, Ruzzo A, Scartozzi M, Santini D et al (2009) PTEN expression and KRAS mutations on primary tumors and metastases in the prediction of benefit from cetuximab plus irinotecan for patients with metastatic colorectal cancer. J Clin Oncol 27(16):2622–2629PubMedCrossRef

12.

Souglakos J, Philips J, Wang R, Marwah S, Silver M, Tzardi M et al (2009) Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer. Br J Cancer 101(3):465–472PubMedCentralPubMedCrossRef

13.

Inno A, Di Salvatore M, Cenci T, Martini M, Orlandi A, Strippoli A et al (2011) Is there a role for IGF1R and c-MET pathways in resistance to cetuximab in metastatic colorectal cancer? Clin Colorectal Cancer 10(4):325–332PubMedCrossRef

14.

Liska D, Chen CT, Bachleitner-Hofmann T, Christensen JG, Weiser MR (2011) HGF rescues colorectal cancer cells from EGFR inhibition via MET activation. Clin Cancer Res 17(3):472–482PubMedCentralPubMedCrossRef

15.

Guo A, Villen J, Kornhauser J, Lee KA, Stokes MP, Rikova K et al (2008) Signaling networks assembled by oncogenic EGFR and c-met. Proc Natl Acad Sci U S A 105(2):692–697PubMedCentralPubMedCrossRef

16.

Bachleitner-Hofmann T, Sun MY, Chen CT, Liska D, Zeng Z, Viale A et al (2011) Antitumor activity of SNX-2112, a synthetic heat shock protein-90 inhibitor, in MET-amplified tumor cells with or without resistance to selective MET inhibition. Clin Cancer Res 17(1):122–133PubMedCentralPubMedCrossRef

17.

Sattler M, Salgia R (2009) The MET axis as a therapeutic target. Update Cancer Ther 3(3):109–118PubMedCentralPubMedCrossRef

18.

Sattler M, Reddy MM, Hasina R, Gangadhar T, Salgia R (2011) The role of the c-met pathway in lung cancer and the potential for targeted therapy. Ther Adv Med Oncol 3(4):171–184PubMedCentralPubMedCrossRef

19.

Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European organization for research and treatment of cancer, national cancer institute of the United States, national cancer institute of Canada. J Natl Cancer Inst 92(3):205–216PubMedCrossRef

20.

Ohnishi H, Ohtsuka K, Ooide A, Matsushima S, Goya T, Watanabe T (2006) A simple and sensitive method for detecting major mutations within the tyrosine kinase domain of the epidermal growth factor receptor gene in non-small-cell lung carcinoma. Diagn Mol Pathol 15(2):101–108PubMedCrossRef

21.

Frattini M, Balestra D, Suardi S, Oggionni M, Alberici P, Radice P et al (2004) Different genetic features associated with colon and rectal carcinogenesis. Clin Cancer Res 10(12 Pt 1):4015–4021PubMedCrossRef

22.

Dua R, Zhang J, Parry G, Penuel E (2011) Detection of hepatocyte growth factor (HGF) ligand-c-MET receptor activation in formalin-fixed paraffin embedded specimens by a novel proximity assay. PLoS ONE 6(1):e15932PubMedCentralPubMedCrossRef

23.

Torres J, Navarro S, Rogla I, Ripoll F, Lluch A, Garcia-Conde J et al (2001) Heterogeneous lack of expression of the tumour suppressor PTEN protein in human neoplastic tissues. Eur J Cancer 37(1):114–121PubMedCrossRef

24.

Murray S, Karavasilis V, Bobos M, Razis E, Papadopoulos S, Christodoulou C et al (2012) Molecular predictors of response to tyrosine kinase inhibitors in patients with non-small-cell lung cancer. J Exp Clin Cancer Res 31(1):77PubMedCentralPubMedCrossRef

25.

Voutsina A, Tzardi M, Kalikaki A, Zafeiriou Z, Papadimitraki E, Papadakis M et al (2012) Combined analysis of KRAS and PIK3CA mutations, MET and PTEN expression in primary tumors and corresponding metastases in colorectal cancer. Mod Pathol 26(2):302–313PubMedCrossRef

26.

Lin B, Utleg AG, Gravdal K, White JT, Halvorsen OJ, Lu W et al (2008) WDR19 expression is increased in prostate cancer compared with normal cells, but low-intensity expression in cancers is associated with shorter time to biochemical failures and local recurrence. Clin Cancer Res 14(5):1397–1406PubMedCrossRef

27.

Halvorsen OJ, Rostad K, Oyan AM, Puntervoll H, Bo TH, Stordrange L et al (2007) Increased expression of SIM2-s protein is a novel marker of aggressive prostate cancer. Clin Cancer Res 13(3):892–897PubMedCrossRef

28.

Takeuchi H, Bilchik A, Saha S, Turner R, Wiese D, Tanaka M et al (2003) C-MET expression level in primary colon cancer: a predictor of tumor invasion and lymph node metastases. Clin Cancer Res 9(4):1480–1488PubMed

29.

De Oliveira AT, Matos D, Logullo AF, Da Silva SR, Neto RA, Filho AL et al (2009) MET is highly expressed in advanced stages of colorectal cancer and indicates worse prognosis and mortality. Anticancer Res 29(11):4807–4811PubMed

30.

Bottaro DP, Rubin JS, Faletto DL, Chan AM, Kmiecik TE, Vande Woude GF et al (1991) Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science 251(4995):802–804PubMedCrossRef

31.

Trusolino L, Comoglio PM (2002) Scatter-factor and semaphorin receptors: cell signalling for invasive growth. Nat Rev Cancer 2(4):289–300PubMedCrossRef

32.

Engelman JA, Zejnullahu K, Gale CM, Lifshits E, Gonzales AJ, Shimamura T et al (2007) PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res 67(24):11924–11932PubMedCrossRef

33.

Adjei AA, Schwartz B, Garmey E (2011) Early clinical development of ARQ 197, a selective, non-ATP-competitive inhibitor targeting MET tyrosine kinase for the treatment of advanced cancers. Oncologist 16(6):788–799PubMedCentralPubMedCrossRef

34.

Liou JM, Wu MS, Shun CT, Chiu HM, Chen MJ, Chen CC et al (2011) Mutations in BRAF correlate with poor survival of colorectal cancers in Chinese population. Int J Colorectal Dis 26(11):1387–1395PubMedCrossRef

35.

Richman SD, Seymour MT, Chambers P, Elliott F, Daly CL, Meade AM et al (2009) KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: results from the MRC FOCUS trial. J Clin Oncol 27(35):5931–5937PubMedCrossRef

Title: Overexpression of MET is a new predictive marker for anti-EGFR therapy in metastatic colorectal cancer with wild-type KRAS
Authors: Tomokazu Kishiki
Hiroaki Ohnishi
Tadahiko Masaki
Kouki Ohtsuka
Yasuo Ohkura
Jyunji Furuse
Takashi Watanabe
Masanori Sugiyama
Publication date: 01-04-2014
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 4/2014
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-014-2401-4

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