Pharmacogenomic and Pharmacoproteomic Studies of Cetuximab in Metastatic Colorectal Cancer: Biomarker Analysis of a Phase I Dose-Escalation Study

Tabernero, Josep; Cervantes, Andrés; Rivera, Fernando; Martinelli, Erika; Rojo, Federico; Heydebreck, Anja von; Macarulla, Teresa; Rodríguez-Braun, Edith; Vega-Villegas, M. E.; Senger, Stefanie; Ramos, Francisco Javier; Roselló, Susana; Çelik, I.; Stroh, Christopher; Baselga, José; Ciardiello, Fortunato

doi:10.1200/jco.2009.22.6043

Cited by 105 publications

(65 citation statements)

References 32 publications

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“…The predictive value of EREG and AREG expression for cetuximab sensitivity was confirmed by Jacobs and colleagues, which analyzed primary tumors from refractory patients with mCRC treated with cetuximab-based therapies (46). Furthermore, in the 045 phase I study of cetuximab monotherapy as first-line treatment of patients with mCRC, Tabernero and colleagues found that AREG and EREG mRNA levels were significantly higher in tumor samples from patients with clinical response to cetuximab as compared with patients with disease progression (47). Although high level of expression of AREG and EREG ligands may predict a better response to treatment with cetuximab in patients with mCRC, HB-EGF and TGF-a overexpression could confer lack of sensitivity to EGFR inhibitors.…”

Section: Discussionmentioning

confidence: 87%

“…Although high level of expression of AREG and EREG ligands may predict a better response to treatment with cetuximab in patients with mCRC, HB-EGF and TGF-a overexpression could confer lack of sensitivity to EGFR inhibitors. In fact, in 045 clinical trial, TGF-a mRNA levels were significantly elevated in the tumors from patients with mCRC with disease progression after cetuximab therapy as compared with patient with clinical response (47). Furthermore, increased HB-EGF may be correlated with cetuximab resistance in head and neck squamous cell carcinoma (48).…”

Section: Discussionmentioning

confidence: 98%

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Increased TGF-α as a Mechanism of Acquired Resistance to the Anti-EGFR Inhibitor Cetuximab through EGFR–MET Interaction and Activation of MET Signaling in Colon Cancer Cells

Troiani

Martinelli

Napolitano

et al. 2013

Clinical Cancer Research

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Purpose: Although cetuximab, an anti-EGF receptor (EGFR) monoclonal antibody, is an effective treatment for patients with KRAS wild-type metastatic colorectal cancer (mCRC), its clinical use is limited by onset of resistance.Experimental Design: We characterized two colorectal cancer models to study the mechanisms of acquired resistance to cetuximab.Results: Following chronic treatment of nude mice bearing cetuximab-sensitive human GEO colon xenografts, cetuximab-resistant GEO (GEO-CR) cells were obtained. In GEO-CR cells, proliferation and survival signals were constitutively active despite EGFR inhibition by cetuximab treatment. Whole gene expression profiling identified a series of genes involved in the hepatocyte growth factor (HGF)-MET-dependent pathways, whichwere upregulated in GEO-CR cells.Furthermore,activated, phosphorylated MET was detected in GEO-CR cells. A second colorectal cancer cell line with acquired resistance to cetuximab was obtained (SW48-CR). Inhibition of MET expression by siRNA restored cetuximab sensitivity in GEO-CR and SW48-CR cells, whereas exogenousactivation ofMETbyHGFstimulationin cetuximab-sensitiveGEOandSW48cells inducedresistance to cetuximab. Treatment of GEO-CR and SW48-CR cells with PHA665752, a selective MET inhibitor, inhibited cell growth, proliferation, and survival signals and impaired cancer cell migration. Overexpression of TGF-a, a specific EGFR ligand, was involved in the acquisition of cetuximab resistance in GEO-CR and SW48-CR cells. In fact, TGF-a overexpression induced the EGFR-MET interaction, with subsequent MET phosphorylation and activation of MET downstream effectors in GEO-CR and SW48-CR cells.Conclusions: These results suggest that overexpression of TGF-a through induction of EGFR-MET interaction contributes to cetuximab resistance in colorectal cancer cells. The combined inhibition of EGFR and MET receptor could represent a strategy for preventing and/or overcoming cetuximab resistance in patients with colorectal cancer.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 98%

Increased TGF-α as a Mechanism of Acquired Resistance to the Anti-EGFR Inhibitor Cetuximab through EGFR–MET Interaction and Activation of MET Signaling in Colon Cancer Cells

Troiani

Martinelli

Napolitano

et al. 2013

Clinical Cancer Research

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133

145

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“…The clinical antitumor activity seen with Sym004 is in line with the superior antitumor activity of Sym004 over cetuximab in preclinical animal models of acquired cetuximab resistance ( 7 , 17 ). In addition, we showed here that Sym004 is highly effi cient at blocking colorectal cancer cell line growth in the presence of the high-affi nity ligands EGF and TGFα, factors known to be both upregulated in response to anti-EGFR antibody treatment and determinants of EGFR inhibitor resistance ( 13 ). We further hypothesize that the pharmacodynamic effects of Sym004, with sustained decrease in EGFR expression in tumor biopsies, relate to the ability of the mAbs to cross-link the EGFR, causing internalization and subsequent degradation of the antibody-receptor complexes ( 17 ).…”

Section: Research Articlementioning

confidence: 81%

Safety and Activity of the First-in-Class Sym004 Anti-EGFR Antibody Mixture in Patients with Refractory Colorectal Cancer

et al. 2015

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Tumor growth in the context of EGFR inhibitor resistance may remain EGFRdependent and is mediated by mechanisms including compensatory ligand upregulation and de novo gene alterations. Sym004 is a two-antibody mixture targeting nonoverlapping EGFR epitopes. In preclinical models, Sym004 causes signifi cant EGFR internalization and degradation, which translates into superior growth inhibition in the presence of ligands. In this phase I trial, we observed grade 3 skin toxicity and hypomagnesemia as mechanism-based dose-limiting events during dose escalation. In dose-expansion cohorts of 9 and 12 mg/kg of Sym004 weekly, patients with metastatic colorectal cancer and acquired EGFR inhibitor resistance were enrolled; 17 of 39 patients (44%) had tumor shrinkage, with 5 patients (13%) achieving partial response. Pharmacodynamic studies confi rmed marked Sym004-induced EGFR downmodulation. MET gene amplifi cation emerged in 1 patient during Sym004 treatment, and a partial response was seen in a patient with EGFR S492R mutation that is predictive of cetuximab resistance. SIGNIFICANCE:Potent EGFR downmodulation with Sym004 in patients with metastatic colorectal cancer and acquired resistance to cetuximab/panitumumab translates into signifi cant antitumor activity and validates the preclinical hypothesis that a proportion of tumors remains dependent on EGFR signaling. Further clinical development and expanded correlative analyses of response patterns with secondary RAS/EGFR mutations are warranted. Cancer Discov; 5(6);[598][599][600][601][602][603][604][605][606][607][608][609]

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“…mCRC patients with a higher gene expression of EREG and AREG prior to treatment tend to have better disease control by cetuximab than low expressers (12). On the other hand, mCRC patients with disease progression have elevated TGFa (13). An increased expression of high-affinity ligands, such as TGFa and HB-EGF, was also observed in a mouse colorectal cancer model with acquired resistance to cetuximab (14).…”

Section: Introductionmentioning

confidence: 89%

GC1118, an Anti-EGFR Antibody with a Distinct Binding Epitope and Superior Inhibitory Activity against High-Affinity EGFR Ligands

Lim¹,

Yoo

Kim³

et al. 2016

Molecular Cancer Therapeutics

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Pharmacogenomic and Pharmacoproteomic Studies of Cetuximab in Metastatic Colorectal Cancer: Biomarker Analysis of a Phase I Dose-Escalation Study

Abstract: Biomarker analysis supported the functional equivalence of weekly and every second week administration of cetuximab and provided further confirmation that patients with KRAS wild-type mCRC were those most likely to benefit from cetuximab treatment.

Cited by 105 publications

References 32 publications

Increased TGF-α as a Mechanism of Acquired Resistance to the Anti-EGFR Inhibitor Cetuximab through EGFR–MET Interaction and Activation of MET Signaling in Colon Cancer Cells

Increased TGF-α as a Mechanism of Acquired Resistance to the Anti-EGFR Inhibitor Cetuximab through EGFR–MET Interaction and Activation of MET Signaling in Colon Cancer Cells

Safety and Activity of the First-in-Class Sym004 Anti-EGFR Antibody Mixture in Patients with Refractory Colorectal Cancer

GC1118, an Anti-EGFR Antibody with a Distinct Binding Epitope and Superior Inhibitory Activity against High-Affinity EGFR Ligands

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