Targeting mechanisms of resistance to anti-EGF receptor therapy in KRAS wild-type colorectal cancer: The path to more personalized medicine

Future Oncology

Volumn 9, Issue 4, 2013, Pages 551-560

  Fakih, Marwan ^a  

^a CITY OF HOPE NATIONAL MEDICAL CENTER   (United States)

Author keywords

BRAF; cetuximab; cMET; colorectal cancer; EGFR; HER; IGFR; panitumumab

Indexed keywords

BEVACIZUMAB; CAPECITABINE; CETUXIMAB; DALOTUZUMAB; EPIDERMAL GROWTH FACTOR RECEPTOR; EPIDERMAL GROWTH FACTOR RECEPTOR 2; EPIDERMAL GROWTH FACTOR RECEPTOR 3; EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR; ERLOTINIB; FLUOROPYRIMIDINE; FLUOROURACIL; FOLINIC ACID; IRINOTECAN; K RAS PROTEIN; OXALIPLATIN; PANITUMUMAB; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PROTEIN KINASE B; RILOTUMUMAB; VEMURAFENIB;

ANTINEOPLASTIC ACTIVITY; CANCER COMBINATION CHEMOTHERAPY; COLORECTAL CANCER; GENE MUTATION; GENE OVEREXPRESSION; HUMAN; LONG TERM EXPOSURE; MAINTENANCE THERAPY; METASTASIS; MOLECULARLY TARGETED THERAPY; OVERALL SURVIVAL; PATIENT SELECTION; PERSONALIZED MEDICINE; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROGRESSION FREE SURVIVAL; PROTEIN EXPRESSION; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; TREATMENT RESPONSE;

ANTIBODIES, MONOCLONAL; COLORECTAL NEOPLASMS; DRUG RESISTANCE, NEOPLASM; GENE EXPRESSION REGULATION, NEOPLASTIC; GENES, RAS; GTP PHOSPHOHYDROLASES; HUMANS; INDIVIDUALIZED MEDICINE; MEMBRANE PROTEINS; MOLECULAR TARGETED THERAPY; MUTATION; PHOSPHATIDYLINOSITOL 3-KINASES; PROTO-ONCOGENE PROTEINS B-RAF; PROTO-ONCOGENE PROTEINS C-MET; PTEN PHOSPHOHYDROLASE; RECEPTOR, EPIDERMAL GROWTH FACTOR; RECEPTOR, ERBB-2; RECEPTOR, ERBB-3;

EID: 84875929136     PISSN: 14796694     EISSN: 17448301     Source Type: Journal    
DOI: 10.2217/fon.12.204     Document Type: Review

References (73)

1. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N. Engl. J. Med. 351, 337-345 (2004). (Pubitemid 38944402)
2. Van Cutsem E, Peeters M, Siena S, et al. Open-label Phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J. Clin. Oncol. 25, 1658-1664 (2007). (Pubitemid 46797944)
3. Peeters M, Price TJ, Cervantes A, et al. Randomized Phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J. Clin. Oncol. 28, 4706-4713 (2010).
4. Sunada H, Magun BE, Mendelsohn J, MacLeod CL. Monoclonal antibody against epidermal growth factor receptor is internalized without stimulating receptor phosphorylation. Proc. Natl Acad. Sci. USA 83, 3825-3829 (1986). (Pubitemid 16062376)
5. Jonker DJ, O'Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. N. Engl. J. Med. 357, 2040-2048 (2007). (Pubitemid 350106711)
6. Bokemeyer C, Bondarenko I, Makhson A, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J. Clin. Oncol. 27, 663-671 (2009).
7. Van Cutsem E, Kohne CH, Lang I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J. Clin. Oncol. 29, 2011-2019 (2011).
8. Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N. Engl. J. Med. 359, 1757-1765 (2008).
9. Fakih M. Anti-EGFR monoclonal antibodies in metastatic colorectal cancer: time for an individualized approach? Expert Rev. Anticancer Ther. 8, 1471-1480 (2008).
10. Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J. Clin. Oncol. 26, 1626-1634 (2008).
11. Peeters M, Price T, Cervantes A, et al. Addition of panitumumab to irinotecan: Results of PICCOLO, a randomized controlled trial in advanced colorectal cancer (aCRC). J. Clin. Oncol. 29, Abstract 3523 (2011).
12. Maughan TS, Adams RA, Smith CG, et al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised Phase 3 MRC COIN trial. Lancet 377, 2103-2114 (2011).
13. Tveit KM, Guren T, Glimelius B, et al. Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. J. Clin. Oncol. 30, 1755-1762 (2012).
14. Douillard JY, Siena S, Cassidy J, et al. Randomized, Phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J. Clin. Oncol. 28, 4697-4705 (2010).
15. Phipps AI, Buchanan DD, Makar KW, et al. BRAF mutation status and survival after colorectal cancer diagnosis according to patient and tumor characteristics. Cancer Epidemiol. Biomarkers Prev. 21(10), 1792-1798 (2012).
16. Imamura Y, Morikawa T, Liao X, et al. Specific Mutations in KRAS codons 12 and 13, and patient prognosis in 1075 BRAF wild-type colorectal cancers. Clin. Cancer Res. 18(17), 4753-4763 (2012).
17. Tol J, Nagtegaal ID, Punt CJ. BRAF mutation in metastatic colorectal cancer. N. Engl. J. Med. 361, 98-99 (2009).
18. De Roock W, De Vriendt V, Normanno N, et al. KRAS, BRAF, PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer. Lancet Oncol. 12, 594-603 (2011).
19. Di Nicolantonio F, Martini M, Molinari F, et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J. Clin. Oncol. 26, 5705-5712 (2008).
20. Lambrechts D, De Roock W, Prenen H, et al. The role of KRAS, BRAF, NRAS, and PIK3CA mutations as markers of resistance to cetuximab in chemorefractory metastatic colorectal cancer. J. Clin. Oncol. 27(15S), Abstract 4020 (2009).
21. Oliner K, Peeters M, Siena S, et al. Evaluation of gene mutations beyond KRAS as predictive biomarkers of response to panitumumab in a randomized, Phase III monotherapy study of metastatic colorectal cancer (mCRC). J. Clin. Oncol. 29(Suppl.), Abstract 3530 (2011).
22. De Roock W, Claes B, Bernasconi D, et al. 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, 753-762 (2010).
23. Saridaki Z, Tzardi M, Papadaki C, et al. 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, e15980 (2011).
24. Sartore-Bianchi A, Martini M, Molinari F, et al. PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res. 69, 1851-1857 (2009).
25. Prenen H, De Schutter J, Jacobs B, et al. PIK3CA mutations are not a major determinant of resistance to the epidermal growth factor receptor inhibitor cetuximab in metastatic colorectal cancer. Clin. Cancer Res. 15, 3184-3188 (2009).
26. Mao C, Yang ZY, Hu XF, et al. PIK3CA exon 20 mutations as a potential biomarker for resistance to anti-EGFR monoclonal antibodies in KRAS wild-type metastatic colorectal cancer: a systematic review and meta-analysis. Ann. Oncol. 23, 1518-1525 (2012).
27. Loupakis F, Pollina L, Stasi I, et al. 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, 2622-2629 (2009).
28. Molinari F, Martin V, Saletti P, et al. Differing deregulation of EGFR and downstream proteins in primary colorectal cancer and related metastatic sites may be clinically relevant. Br. J. Cancer 100, 1087-1094 (2009).
29. Montagut C, Dalmases A, Bellosillo B, et al. Identification of a mutation in the extracellular domain of the epidermal growth factor receptor conferring cetuximab resistance in colorectal cancer. Nat. Med. 18, 221-223 (2012).
30. Wadlow RC, Hezel AF, Abrams TA, et al. Panitumumab in patients with KRAS wild-type colorectal cancer after progression on cetuximab. Oncologist 17, 14 (2012).
31. Khambata-Ford S, Garrett CR, Meropol NJ, et al. Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J. Clin. Oncol. 25, 3230-3237 (2007). (Pubitemid 47325606)
32. Prenen H, Jacobs B, De Roock W, et al. Use of amphiregulin and epiregulin mRNA expression in primary tumors to predict outcome in metastatic colorectal cancer treated with cetuximab. J. Clin. Oncol. 27(15S), Abstract 4020 (2009).
33. Stintzing S, Jung A, Kapaun C, et al. Ligand expression of the EGFR ligands amphiregulin, epiregulin, and amplification of the EGFR gene to predict for treatment efficacy in KRAS wild-type mCRC patients treated with cetuximab plus CAPIRI and CAPOX: analysis of the randomized AIO CRC-0104 trial. J. Clin. Oncol. 30(Suppl.), Abstract 3519 (2012).
34. Adams R, Fisher D, Farragher S, et al. Epiregulin (EREG) and amphiregulin (AREG) gene expression to predict response to cetuximab therapy in combination with oxaliplatin (Ox) and 5FU in first-line treatment of advanced colorectal cancer (aCRC). J. Clin. Oncol. 30(Suppl.), Abstract 3516 (2012).
35. Simon I, Tian S, Moreno V, et al. The role of activating mutations of KRAS, BRAF, and PIK3CA pathway convergence at the transcriptional level and prediction of treatment response to cetuximab in colorectal cancer. J. Clin. Oncol. 29(Suppl.), Abstract 3534 (2011).
36. Popovici V, Budinska E, Tejpar S, et al. Identification of a poor-prognosis BRAF-mutant-like population of patients with colon cancer. J. Clin. Oncol. 30, 1288-1295 (2012).
37. Gherardi E, Birchmeier W, Birchmeier C, Vande Woude G. Targeting MET in cancer: rationale and progress. Nat. Rev. Cancer 12, 89-103 (2012).
38. Di Renzo MF, Olivero M, Giacomini A, et al. Overexpression and amplification of the met/HGF receptor gene during the progression of colorectal cancer. Clin. Cancer Res. 1, 147-154 (1995).
39. Kammula US, Kuntz EJ, Francone TD, et al. Molecular co-expression of the c-Met oncogene and hepatocyte growth factor in primary colon cancer predicts tumor stage and clinical outcome. Cancer Lett. 248, 219-228 (2007). (Pubitemid 46330555)
40. Krumbach R, Schuler J, Hofmann M, et al. Primary resistance to cetuximab in a panel of patient-derived tumour xenograft models: activation of MET as one mechanism for drug resistance. Eur. J. Cancer 47, 1231-1243 (2011).
41. Morgillo F, Kim WY, Kim ES, et al. Implication of the insulin-like growth factor- IR pathway in the resistance of non-small cell lung cancer cells to treatment with gefitinib. Clin. Cancer Res. 13, 2795-2803 (2007). (Pubitemid 46788049)
42. Barnes CJ, Ohshiro K, Rayala SK, et al. Insulin-like growth factor receptor as a therapeutic target in head and neck cancer. Clin. Cancer Res. 13, 4291-4299 (2007). (Pubitemid 47105993)
43. Slomiany MG, Black LA, Kibbey MM, et al. Insulin-like growth factor-1 receptor and ligand targeting in head and neck squamous cell carcinoma. Cancer Lett. 248, 269-279 (2007). (Pubitemid 46330562)
44. Reidy DL, Vakiani E, Fakih MG, et al. Randomized, Phase II study of the insulin-like growth factor-1 receptor inhibitor IMC-A12, with or without cetuximab, in patients with cetuximab- or panitumumab-refractory metastatic colorectal cancer. J. Clin. Oncol. 28, 4240-4246 (2010).
45. Watkins D, Tabernero J, Schmoll H, et al. A randomized Phase II/III study of the anti-IGF-1R antibody MK-0646 (dalotuzumab) in combination with cetuximab (Cx) and irinotecan (Ir) in the treatment of chemorefractory metastatic colorectal cancer (mCRC) with wild-type (wt) KRAS status. J. Clin. Oncol. 29(Suppl.), Abstract 3501 (2011).
46. Laurent-Puig P, Manceau G, Zucman-Rossi J, Blons H. Dual blockade of epidermal growth factor receptor-induced pathways: a new avenue to treat metastatic colorectal cancer. J. Clin. Oncol. 30, 1550-1552 (2012).
47. Beji A, Horst D, Engel J, et al. Toward the prognostic significance and therapeutic potential of HER3 receptor tyrosine kinase in human colon cancer. Clin. Cancer Res. 18, 956-968 (2012).
48. Scartozzi M, Mandolesi A, Giampieri R, et al. The role of HER-3 expression in the prediction of clinical outcome for advanced colorectal cancer patients receiving irinotecan and cetuximab. Oncologist 16, 53-60 (2011).
49. Scartozzi M, Giampieri R, Maccaroni E, et al. Analysis of HER-3, insulin growth factor-1, nuclear factor-kB and epidermal growth factor receptor gene copy number in the prediction of clinical outcome for K-RAS wild-type colorectal cancer patients receiving irinotecan-cetuximab. Ann. Oncol. 23, 1706-1712 (2012).
50. Ooi A, Takehana T, Li X, et al. Protein overexpression and gene amplification of HER-2 and EGFR in colorectal cancers: an immunohistochemical and fluorescent in situ hybridization study. Mod. Pathol. 17, 895-904 (2004). (Pubitemid 38993773)
51. Al-Kuraya K, Novotny H, Bavi P, et al. HER2, TOP2A, CCND1, EGFR and C-MYC oncogene amplification in colorectal cancer. J. Clin. Pathol. 60, 768-772 (2007). (Pubitemid 47056905)
52. Marx AH, Burandt EC, Choschzick M, et al. Heterogenous high-level HER-2 amplification in a small subset of colorectal cancers. Hum. Pathol. 41, 1577-1585 (2010).
53. Barbara C, Martin V, Molinari F, et al. Use of HER2 gene amplification to identify patients with metastatic colorectal cancer resistant to anti-EGFR monoclonal antibodies. J. Clin. Oncol. 30(Suppl. 4), Abstract 474 (2012).
54. Yonesaka K, Zejnullahu K, Okamoto I, et al. Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab. Sci. Transl Med. 3(99), 99ra86 (2011).
55. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 364, 2507-2516 (2011).
56. Kopetz S, Desai J, Chan E, et al. PLX4032 in metastatic colorectal cancer patients with mutant BRAF tumors. J. Clin. Oncol. 28, Abstract 3534 (2010).
57. Prahallad A, Sun C, Huang S, et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 483, 100-103 (2012).
58. Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat. Rev. Cancer 9, 550-562 (2009).
59. Juric D, Rodon II J, Gonzalez-Angulo A, et al. BYL719, a next generation PI3K alpha specific inhibitor: preliminary safety, PK, and efficacy results from the first-in-human study. Cancer Res. 72(Suppl. 8), Abstract CT-01 (2012).
60. 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. 72, 3228-3237 (2012).
61. Khalili JS, Yu X, Wang J, et al. Combination small molecule MEK and PI3K inhibition enhances uveal melanoma cell death in a mutant GNAQ- and GNA11-dependent manner. Clin. Cancer Res. 18, 4345-4355 (2012).
62. Haagensen EJ, Kyle S, Beale GS, et al. The synergistic interaction of MEK and PI3K inhibitors is modulated by mTOR inhibition. Br. J. Cancer 106, 1386-1394 (2012).
63. Shimizu T, Tolcher AW, Papadopoulos KP, et al. The clinical effect of the dual-targeting strategy involving PI3K/AKT/mTOR and RAS/MEK/ERK pathways in patients with advanced cancer. Clin. Cancer Res. 18, 2316-2325 (2012).
64. Eng C, Van Cutsem E, Nowara E, et al. A randomized, Phase Ib/II trial of rilotumumab (AMG 102; ril) or ganitumab (AMG 479; gan) with panitumumab (pmab) versus pmab alone in patients (pts) with wild-type (WT) KRAS metastatic colorectal cancer (mCRC): primary and biomarker analyses. J. Clin. Oncol. 29(Suppl.), Abstract 3500 (2011).
65. Oliner K, Tang R, Anderson A, et al. Evaluation of MET pathway biomarkers in a Phase II study of rilotumumab (R, AMG 102) or placebo (P) in combination with epirubicin, cisplatin, and capecitabine (ECX) in patients (pts) with locally advanced or metastatic gastric (G) or esophagogastric junction (EGJ) cancer. J. Clin. Oncol. 30(Suppl.), Abstract 4005 (2012).
66. Rimassa L, Porta C, Borbath I, et al. Tivantinib (ARQ 197) versus placebo in patients (Pts) with hepatocellular carcinoma (HCC) who failed one systemic therapy: results of a randomized controlled Phase II trial (RCT). J. Clin. Oncol. 30(Suppl.), Abstract 4006 (2012).
67. Watkins D, Ayers M, Cunningham D, et al. Molecular analysis of the randomized Phase II/III study of the anti-IGF-1R antibody dalotuzumab (MK-0646) in combination with cetuximab (Cx) and irinotecan (Ir) in the treatment of chemorefractory KRAS wild-type metastatic colorectal cancer (mCRC). J. Clin. Oncol. 30(Suppl.), Abstract 3531 (2012).
68. Weickhardt AJ, Price TJ, Chong G, et al. Dual targeting of the epidermal growth factor receptor using the combination of cetuximab and erlotinib: preclinical evaluation and results of the Phase II DUX study in chemotherapy-refractory, advanced colorectal cancer. J. Clin. Oncol. 30, 1505-1512 (2012).
69. Tournigand C, Samson B, Scheithauer W, et al. Bevacizumab (Bev) with or without erlotinib as maintenance therapy, following induction first-line chemotherapy plus Bev, in patients (pts) with metastatic colorectal cancer (mCRC): efficacy and safety results of the International GERCOR DREAM Phase III trial. J. Clin. Oncol. 30(18), Abstract LBA3500 (2012).
70. Brand TM, Dunn EF, Iida M, et al. Erlotinib is a viable treatment for tumors with acquired resistance to cetuximab. Cancer Biol. Ther. 12, 436-446 (2011).
71. Anido J, Matar P, Albanell J, et al. ZD1839, a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, induces the formation of inactive EGFR/HER2 and EGFR/HER3 heterodimers and prevents heregulin signaling in HER2-overexpressing breast cancer cells. Clin. Cancer Res. 9, 1274-1283 (2003). (Pubitemid 36418377)
72. Schaefer G, Shao L, Totpal K, Akita RW. Erlotinib directly inhibits HER2 kinase activation and downstream signaling events in intact cells lacking epidermal growth factor receptor expression. Cancer Res. 67, 1228-1238 (2007).
73. Bertotti A, Migliardi G, Galimi F, et al. A molecularly annotated platform of patient-derived xenografts ("xenopatients") identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer Discov. 1, 508-523 (2011).