Resistance to EGFR-Targeted Therapy: A Family Affair

Purpose: In colorectal cancer, the activation of the intracellular RAS-RAF and PIK3CA-AKT pathways has been implicated in the resistance to anti-EGFR mAbs. We have investigated the role of regorafenib, an oral multikinase inhibitor, in combination with cetuximab, an anti-EGFR mAb, to overcome anti-EGFR resistance.Experimental Design: We have tested, in vitro and in vivo, the effects of regorafenib in a panel of human colorectal cancer cell lines with a KRAS mutation (SW480, SW620, HCT116, LOVO, and HCT15) or with a BRAF mutation (HT29), as models of intrinsic resistance to cetuximab treatment, and in two human colorectal cancer cell lines (GEO and SW48) that are cetuximabsensitive, as well as in their derived cells with acquired resistance to cetuximab (GEO-CR and SW48-CR).Results: Treatment with regorafenib determined a dose-dependent growth inhibition in all colorectal cancer cell lines. The combined treatment with cetuximab and regorafenib induced synergistic antiproliferative and apoptotic effects in cetuximabresistant cell lines by blocking MAPK and AKT pathways. Nude mice were injected s.c. with HCT116, HCT15, GEO-CR, and SW48-CR cells. The combined treatment caused significant tumor growth inhibition. Synergistic antitumor activity of regorafenib plus cetuximab was also observed in an orthotopic colorectal cancer model of HCT116 cells. In particular, the combined treatment induced a significant tumor growth inhibition in the primary tumor site (cecum) and completely prevented metastasis formation.Conclusions: The combined treatment with cetuximab and regorafenib could be a strategy to overcome resistance to anti-EGFR therapies in metastatic colorectal cancer patients. Clin Cancer Res; 21(13); 2975-83. Ó2015 AACR.

Section: Introductionmentioning

confidence: 99%

Primary and Acquired Resistance of Colorectal Cancer to Anti-EGFR Monoclonal Antibody Can Be Overcome by Combined Treatment of Regorafenib with Cetuximab

Napolitano

Martini

Rinaldi³

et al. 2015

“…Many patients manifest intrinsic resistance, and some who initially respond to treatment subsequently develop progressive disease (acquired resistance). Accumulating evidence suggests that potential mechanisms of acquired resistance involve HER signaling plasticity, amplification, and/or compensatory signaling of other receptor tyrosine kinases (RTK) in the presence of single receptor inhibition (10,11). The majority of FDA-approved HER family monoclonal antibodies target single receptors (cetuximab and panitumumab against EGFR; trastuzumab and pertuzumab against HER2).…”

Section: Introductionmentioning

confidence: 99%

Pan-HER Inhibitor Augments Radiation Response in Human Lung and Head and Neck Cancer Models

Francis

Huang

Armstrong

et al. 2016

Purpose: Aberrant regulation of the EGF receptor family (EGFR, HER2, HER3, HER4) contributes to tumorigenesis and metastasis in epithelial cancers. Pan-HER represents a novel molecular targeted therapeutic composed of a mixture of six monoclonal antibodies against EGFR, HER2, and HER3.Experimental Design: In the current study, we examine the capacity of Pan-HER to augment radiation response across a series of human lung and head and neck cancers, including EGFR inhibitor-resistant cell lines and xenografts.Results: Pan-HER demonstrates superior antiproliferative and radiosensitizing impact when compared with cetuximab. The mechanisms underlying these effects appear to involve attenuation of DNA damage repair, enhancement of programmed cell death, cell-cycle redistribution, and induction of cellular senescence. Combined treatment of Pan-HER with single or fractionated radiation in human tumor xenografts reveals a potent antitumor and regrowth delay impact compared with Pan-HER or radiation treatment alone.Conclusions: These data highlight the capacity of Pan-HER to augment radiation response in lung and head and neck cancer models and support investigation of Pan-HER combined with radiation as a promising clinical therapeutic strategy.

“…Accumulating evidence shows that the HER family displays a high degree of plasticity and provides compensatory signaling leading to acquired resistance in response to therapeutic intervention (10,11). Examples include HER family TKI (gefitinib and erlotinib) resistance in HER2-driven breast cancer due to increased HER3 expression (12), anti-HER2 trastuzumab resistance in breast cancer due to overexpression of EGFR and EGFR ligands (13) or increased EGFR and/or HER3 expression (14), EGFR/HER2 TKI lapatinib resistance in breast cancer due to HER3 upregulation (15), and anti-EGFR cetuximab resistance in colorectal cancer mediated by upregulation of HER2 or HER3 ligand neuregulin (heregulin; ref.…”

Section: Introductionmentioning

confidence: 99%

Pan-HER, an Antibody Mixture Simultaneously Targeting EGFR, HER2, and HER3, Effectively Overcomes Tumor Heterogeneity and Plasticity

Jacobsen

Poulsen

Dahlman

et al. 2015

Purpose: Accumulating evidence indicates a high degree of plasticity and compensatory signaling within the human epidermal growth factor receptor (HER) family, leading to resistance upon therapeutic intervention with HER family members.Experimental Design/Results: We have generated Pan-HER, a mixture of six antibodies targeting each of the HER family members EGFR, HER2, and HER3 with synergistic pairs of antibodies, which simultaneously remove all three targets, thereby preventing compensatory tumor promoting mechanisms within the HER family. Pan-HER induces potent growth inhibition in a range of cancer cell lines and xenograft models, including cell lines with acquired resistance to therapeutic antibodies. Pan-HER is also highly efficacious in the presence of HER family ligands, indicating that it is capable of overcoming acquired resistance due to increased ligand production. All three target specificities contribute to the enhanced efficacy, demonstrating a distinct benefit of combined HER family targeting when compared with single-receptor targeting.Conclusions: Our data show that simultaneous targeting of three receptors provides broader efficacy than targeting a single receptor or any combination of two receptors in the HER family, especially in the presence of HER family ligands. Pan-HER represents a novel strategy to deal with primary and acquired resistance due to tumor heterogeneity and plasticity in terms of HER family dependency and as such may be a viable alternative in the clinic.