Erlotinib is a viable treatment for tumors with acquired resistance to cetuximab

Brand, Toni M.; Dunn, Emily F.; Iida, Mari; Myers, Rebecca; Kostopoulos, Kellie T.; Li, Chunrong; Peet, Chimera R.; Wheeler, Deric L.

doi:10.4161/cbt.12.5.16394

Cited by 16 publications

(19 citation statements)

References 54 publications

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“…Once cetuximab-resistant tumors reached a volume of ~800 mm 3 , mice were grouped according to tumor size at the time of resistance. Cetuximabresistant tumors were observed in 28 of 40 mice (70 %), which is in line with previous studies (14,20,21). Mice were then randomly subdivided into 13 cetuximab-resistant xenograft groups (28 mice in total), nine of which are shown in Figure 5A.…”

Section: Pan-her Delays the Growth Of Tumors With Acquired Cetuximab-supporting

confidence: 56%

Targeting the HER family with Pan-HER effectively overcomes resistance to cetuximab

Iida¹,

Bahrar²,

Brand³

et al. 2016

European Journal of Cancer

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Section: Pan-her Delays the Growth Of Tumors With Acquired Cetuximab-supporting

confidence: 56%

Targeting the HER family with Pan-HER effectively overcomes resistance to cetuximab

Iida¹,

Bahrar²,

Brand³

et al. 2016

European Journal of Cancer

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“…Ctx R clones are known to be highly dependent on EGFR for proliferation (30-32). To determine if AXL also plays a role in Ctx R cell proliferation, proliferation assays were performed 72 hours post-transfection with a pooled AXL-siRNA (siAXL) or non-targeting siRNA (siNT) ( Figure 2A ).…”

Section: Resultsmentioning

confidence: 99%

“…The HNSCC cell line UM-SCC1 was provided by Dr. Thomas E. Carey (University of Michigan, Ann Harbor, MI) and maintained in 10% FBS in Dulbecco's modified Eagle's medium (DMEM) with 1% penicillin and streptomycin. The development of Ctx R cells has been previously described (30-32). All Ctx R cell lines were validated to express wild type (WT) EGFR by sequencing.…”

Section: Methodsmentioning

confidence: 99%

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AXL Mediates Resistance to Cetuximab Therapy

et al. 2014

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The EGFR antibody cetuximab is used to treat numerous cancers, but intrinsic and acquired resistance to this agent is a common clinical problem. In this study we show that overexpression of the oncogenic receptor kinase AXL is sufficient to mediate acquired resistance to cetuximab in models of non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC), where AXL was overexpressed, activated and tightly associated with EGFR expression in cells resistant to cetuximab (CtxR cells). Using RNAi methods and novel AXL targeting agents, we found that AXL activation stimulated cell proliferation, EGFR activation and MAPK signaling in CtxR cells. Notably, EGFR directly regulated the expression of AXL mRNA through MAPK signaling and the transcription factor c-Jun in CtxR cells, creating a positive feedback loop that maintained EGFR activation by AXL. Cetuximab-sensitive parental cells were rendered resistant to cetuximab by stable overexpression of AXL or stimulation with EGFR ligands, the latter of which increased AXL activity and association with the EGFR. In tumor xenograft assays, the development of resistance following prolonged treatment with cetuximab was associated with AXL hyperactivation and EGFR association. Furthermore, in an examination of patient-derived xenografts established from surgically resected HNSCCs, AXL was overexpressed and activated in tumors that displayed intrinsic resistance to cetuximab. Collectively, our results identify AXL as a key mediator of cetuximab resistance, providing a rationale for clinical evaluation of AXL targeting drugs to treat cetuximab-resistant cancers.

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“…We previously tested several small molecule inhibitors including gefitinib and erlotinib and reported that cetuximab resistant tumors may still rely on EGFR for growth and survival and can be successfully targeted via alternative EGFR TKIs (18, 25). Researchers began investigating natural compounds as a means to overcome resistance in part because there is lower toxicity associated with these compounds when compared to established targeted therapies (26).…”

Section: Introductionmentioning

confidence: 99%

Overcoming Resistance to Cetuximab with Honokiol, A Small-Molecule Polyphenol

Pearson

Iida

Orbuch

et al. 2018

Molecular Cancer Therapeutics

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Overexpression and activation of the Epidermal Growth Factor Receptor (EGFR) have been linked to poor prognosis in several human cancers. Cetuximab is a monoclonal antibody against EGFR, that is used for the treatment in head and neck squamous cell carcinoma (HNSCC) and metastatic colorectal cancer. Unfortunately, most tumors have intrinsic or acquire resistance to cetuximab during the course of therapy. Honokiol is a natural compound found in the bark and leaves of the Chinese Magnolia tree and is established to have several anti-cancer properties without appreciable toxicity. In this study, we hypothesized that combining cetuximab and honokiol treatments could overcome acquired resistance to cetuximab. We previously developed a model of acquired resistance to cetuximab in non-small cell lung cancer H226 cell line. Treatment of cetuximab resistant clones with honokiol and cetuximab resulted in a robust anti-proliferative response. Immunoblot analysis revealed the HER family and their signaling pathways were downregulated after combination treatment, most notably the proliferation (MAPK) and survival (AKT) pathways. Additionally, we found a decrease in phosphorylation of DRP1 and reactive oxygen species after combination treatment in cetuximab resistant clones which may signify a change in mitochondrial function. Furthermore, we utilized cetuximab resistant HNSCC patient derived xenografts (PDX) to test the benefit of combinatorial treatment in vivo. There was significant growth delay in PDX tumors after combination treatment with a subsequent down-regulation of active MAPK, AKT, and DRP1 signaling as seen in vitro. Collectively these data suggest that honokiol is a promising natural compound in overcoming acquired resistance to cetuximab.

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Erlotinib is a viable treatment for tumors with acquired resistance to cetuximab

Cited by 16 publications

References 54 publications

Targeting the HER family with Pan-HER effectively overcomes resistance to cetuximab

Targeting the HER family with Pan-HER effectively overcomes resistance to cetuximab

AXL Mediates Resistance to Cetuximab Therapy

Overcoming Resistance to Cetuximab with Honokiol, A Small-Molecule Polyphenol

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