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Inductive mechanisms limiting response to anti-epidermal growth factor receptor therapy

Hutcheson, Iain Robert, Knowlden, Janice Mary, Jones, Helen E., Burmi, R. S., McClelland, Richard Andrew, Barrow, Denise, Gee, Julia Margaret Wendy and Nicholson, Robert Ian 2006. Inductive mechanisms limiting response to anti-epidermal growth factor receptor therapy. Endocrine-Related Cancer 13 (S1) , S89-S97. 10.1677/erc.1.01279

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Abstract

Aberrant epidermal growth factor receptor (EGFR) signalling, a key feature of a variety of human malignancies, can drive a range of mechanisms underlying tumour growth and progression, including increased cell proliferation, angiogenesis, metastasis and decreased apoptosis. Anti-EGFR therapies, as monotherapies and in combination with chemotherapy, have proved effective in inhibiting these processes both in the clinical and in the preclinical settings. However, only a small cohort of patients have derived significant benefit from this therapy, with both de novo and acquired resistance to these agents evident in a number of recent studies. If we are to improve the effectiveness of such targeted therapies, then there is an urgent need to understand the resistance mechanisms. Here, we describe both non-genomic and genomic mechanisms of resistance to the selective EGFR tyrosine kinase inhibitor gefitinib (IRESSA), which we have identified initially in an EGFR-positive tamoxifen-resistant MCF-7 breast cancer cell line, but more recently in other EGFR-positive cancer types. Importantly, we show that gefitinib, in common with anti-hormonal agents, is not a passive bystander in the cellular response to drug treatment, but plays an active role in promoting signalling pathways that serve to limit its anti-tumour activity and maintain the cellular cohort from which acquired resistance can ultimately evolve. These findings indicate that inductive signalling is an important determinant of response to EGFR-targeted therapies and deciphering such pathways may provide us with the opportunity to design more effective strategies to combat resistance mechanisms and improve response to initial therapy.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Biosciences
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
R Medicine > RM Therapeutics. Pharmacology
Additional Information: This paper was presented at the 2nd Tenovus/AstraZeneca Workshop, Cardiff (2006). AstraZeneca supported the meeting and the Welsh School of Pharmacy, Cardiff University has supported the publication of these proceedings.
Publisher: Society for Endocrinology
ISSN: 1351-0088
Last Modified: 12 Jun 2019 02:10
URI: http://orca-mwe.cf.ac.uk/id/eprint/17211

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