Increased signalling of EGFR and IGF1R, and deregulation of PTEN/PI3K/Akt pathway are related with trastuzumab resistance in HER2 breast carcinomas

Gallardo, Alberto; Lerma, Enrique; Escuín, Daniel; Tibau, Ariadna; Muñoz, Josefina; Ojeda, B.; Barnadas, A.; Adrover, Encarna; Sánchez-Tejada, Laura; Giner, Daniel; Ortiz-Martínez, Fernando; Peiró, Gloria

doi:10.1038/bjc.2012.85

Cited by 212 publications

(181 citation statements)

References 53 publications

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“…In MET-addicted gastric cancer, activation of HER family members was poorly responsive to MET inhibitor [29]. In HER2-overexpressing breast cancer, the insulin-like growth factor receptor, other human epidermal growth factor receptor family members (EGFR, HER3) and MET overexpression might be critical for treatmentacquired resistance to trastuzumab [30][31][32]. In lung cancer, drug resistance to EGFR-TKI was associated with MET amplification [33,34].…”

Section: Discussionmentioning

confidence: 99%

Expression profiles of HER2, EGFR, MET and FGFR2 in a large cohort of patients with gastric adenocarcinoma

et al. 2014

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Background Some tyrosine kinase receptors (RTKs) play critical roles in gastric cancer progression. Not only trastuzumab, but also several other agents targeting RTKs are being investigated for gastric cancer therapy. However, the simultaneous expression of multiple RTKs, which may interfere with the effectiveness of therapeutic agents, has not been evaluated in a large cohort with gastric adenocarcinoma (GAC). Methods We performed a tissue microarray analysis in 950 patients with GAC who underwent a gastrectomy without preoperative chemotherapy. The protein expressions of HER2, EGFR, MET and FGFR2 were evaluated using immunohistochemistry, and the gene amplifications of HER2, EGFR and MET were examined using dual-color in situ hybridization.Results The frequency of overexpression was 11.8 % for HER2, 23.5 % for EGFR, 24.9 % for MET and 31.1 % for FGFR2. Whereas strong staining for each of the RTKs was heterogeneous, tumors with homogeneously strong staining areas often exhibited gene amplification. Strong EGFR expression was significantly associated with a poor outcome, but no prognostic correlations were observed in other RTKs. The overexpression of single and multiple RTKs was observed in 40.4 and 22.7 % of the cases, respectively. HER2, EGFR, MET and FGFR2 predominance was observed in 10.1, 13.9, 16.1 and 22.9 % of the GACs, respectively. Conclusions Approximately two-thirds of patients with GAC exhibited the expression of at least one RTK and would be candidates for targeted therapies. Moreover, one-third of at least one RTK overexspressing cases showed multiple RTKs expression. Our results may be useful for selecting the most suitable patients for each targeted therapy.

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Section: Discussionmentioning

confidence: 99%

Expression profiles of HER2, EGFR, MET and FGFR2 in a large cohort of patients with gastric adenocarcinoma

et al. 2014

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“…These results suggest that breast cancer cells with dual MET and ERBB2 expression are likely to be resistant to targeted therapy toward ERBB2 or MET alone. ERBB2 þ breast cancers (26,27), and have been shown to play a role in trastuzumab resistance (28,29). In addition, EGFR and ERBB3 can promote the resistance of METaddicted gastric carcinomas to MET inhibitors (23).…”

Section: Met and Erbb2 Compensate For Each Other During Targeted Knocmentioning

confidence: 99%

MET and ERBB2 Are Coexpressed in ERBB2+ Breast Cancer and Contribute to Innate Resistance

Paulson

Linklater

Berghuis

et al. 2013

Molecular Cancer Research

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Breast cancer displays significant intratumoral heterogeneity, which has been shown to have a substantial impact on both innate and acquired resistance to tyrosine kinase inhibitors. The heterogeneous expression of multiple receptor tyrosine kinases (RTK) in cancers supports tumor signaling robustness and plays a significant role in resistance to targeted inhibition. Recent studies have revealed interactions between the MET receptor and the ERBB receptor family in the therapeutic resistance of several cancers. In this study, the relationship between MET expression/activity and the expression/activity of the ERBB receptor family in human breast cancer was interrogated. Importantly, a significant percentage of ERBB2 þ tumors coexpressing MET and ERBB2 were observed and displayed significant heterogeneity with subpopulations of cells that are MET À / ERBB2 þ , MET þ /ERBB2 À , and MET þ /ERBB2 þ . In a MET þ /ERBB2 þ breast cancer cell line, MET depletion resulted in increased ERBB2 activation, and conversely, ERBB2 depletion resulted in increased MET activation. Neither EGFR nor ERBB3 compensated for MET or ERBB2 knockdown. The loss of either MET or ERBB2 led to a decrease in PI3K/AKT signaling and increased dependency on MAPK. These data show that a subset of ERBB2 þ breast cancers express MET and contain MET þ /ERBB2 þ subpopulations. Moreover, analysis of RTK activation during ERBB2 knockdown indicated that MET signaling is a compensatory pathway of resistance.

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“…Preclinical evidence supports a role for IGF-IR in reducing the effectiveness of anti-ErbB2 and anti-EGFR therapies, requiring coblockade of the PI3K/AKT/mTOR cascade (14)(15)(16). Addition of the IGF-I ligand has been shown to protect trastuzumab-sensitive cells from cell death (17), and patients treated with trastuzumab who also express IGF-IR have shorter progression-free survival (18). Not surprisingly, IGF-IR and EGFR/ErbB2 therapies were combined in multiple clinical trials (19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

MM-141, an IGF-IR– and ErbB3-Directed Bispecific Antibody, Overcomes Network Adaptations That Limit Activity of IGF-IR Inhibitors

Fitzgerald

Johnson

Baum

et al. 2014

Molecular Cancer Therapeutics

102

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Although inhibition of the insulin-like growth factor (IGF) signaling pathway was expected to eliminate a key resistance mechanism for EGF receptor (EGFR)-driven cancers, the effectiveness of IGF-I receptor (IGF-IR) inhibitors in clinical trials has been limited. A multiplicity of survival mechanisms are available to cancer cells. Both IGF-IR and the ErbB3 receptor activate the PI3K/AKT/mTOR axis, but ErbB3 has only recently been pursued as a therapeutic target. We show that coactivation of the ErbB3 pathway is prevalent in a majority of cell lines responsive to IGF ligands and antagonizes IGF-IR-mediated growth inhibition. Blockade of the redundant IGF-IR and ErbB3 survival pathways and downstream resistance mechanisms was achieved with MM-141, a tetravalent bispecific antibody antagonist of IGF-IR and ErbB3. MM-141 potency was superior to monospecific and combination antibody therapies and was insensitive to variation in the ratio of IGF-IR and ErbB3 receptors. MM-141 enhanced the biologic impact of receptor inhibition in vivo as a monotherapy and in combination with the mTOR inhibitor everolimus, gemcitabine, or docetaxel, through blockade of IGF-IR and ErbB3 signaling and prevention of PI3K/AKT/mTOR network adaptation. Mol Cancer Ther; 13(2); 410-25. Ó2013 AACR.

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Increased signalling of EGFR and IGF1R, and deregulation of PTEN/PI3K/Akt pathway are related with trastuzumab resistance in HER2 breast carcinomas

Cited by 212 publications

References 53 publications

Expression profiles of HER2, EGFR, MET and FGFR2 in a large cohort of patients with gastric adenocarcinoma

Expression profiles of HER2, EGFR, MET and FGFR2 in a large cohort of patients with gastric adenocarcinoma

MET and ERBB2 Are Coexpressed in ERBB2+ Breast Cancer and Contribute to Innate Resistance

MM-141, an IGF-IR– and ErbB3-Directed Bispecific Antibody, Overcomes Network Adaptations That Limit Activity of IGF-IR Inhibitors

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