Schedule-dependent effects of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib in combination with the mammalian target of rapamycin (mTOR) inhibitor everolimus (RAD001)

Cosimo, Serena Di; Matar, Pablo; Rojo, Federico; Guzmán, Marta; Rodríguez, Solange; Jimenez, J.; Arribas, J.; Cognetti, F.; Lane, Heidi A.; Baselga, J.

doi:10.1200/jco.2004.22.14_suppl.3074

Cited by 11 publications

(7 citation statements)

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“…A previous report [60] has evidenced the activation of 4EBP1 by an EGFR TK inhibitor, EKI-785, thus decreasing the inhibitory interaction of 4EBP1 to eIF4E, indicating that EGFR TK inhibitors may paradoxically promote the translation of complex 5'UTR-containing transcripts, some of which encode for proteins involved in driving cell proliferation. Consistent with these data, combined treatment with mTOR inhibitors and anti-EGFR TKIs has shown promising activity [37,61].…”

Section: Constitutive Activation Of Downstream Pathwayssupporting

confidence: 58%

Resistance mechanisms of tumour cells to EGFR inhibitors

et al. 2009

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In spite of the overexpression and efficient inhibition of epidermal growth factor receptor (EGFR), resistance to EGFR inhibitors, monoclonal antibodies and tyrosine kinase inhibitors may occur. Understanding the molecular mechanisms affecting cancer cell sensitivity or resistance to EGFR inhibitors may be of help in deciding on treatment and in new translational studies. This review will focus on the most relevant mechanisms contributing to the acquisition of sensitivity/resistance to EGFR inhibitors.

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Section: Constitutive Activation Of Downstream Pathwayssupporting

confidence: 58%

Resistance mechanisms of tumour cells to EGFR inhibitors

et al. 2009

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“…Different effects were observed in MDA-MB-145 cells, which are relatively resistant to gefitinib. In this case, simultaneous treatment induced synergistic effects, whereas the sequential approach with gefitinib followed by RAD001 produced additive effects [70]. Therefore, mTOR inhibition appears to potentiate the effects of the EGFR inhibitor gefitinib in a schedule-dependent fashion.…”

Section: Discussionmentioning

confidence: 97%

PI3K/Akt/mTOR pathway as a target for cancer therapy

Morgensztern¹,

McLeod²

2005

Anti-Cancer Drugs

411

280

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The PI3K/Akt/mTOR pathway regulates several normal cellular functions that are also critical for tumorigenesis, including cellular proliferation, growth, survival and mobility. Components of this pathway are frequently abnormal in a variety of tumors, making them an attractive target for anti-cancer therapy. Inhibition of mTOR in patients with cancer became more feasible after the development of rapamycin analogs with improved pharmacologic properties. The promising activity of these agents in early clinical trials has led to the development of ongoing phase III trials in renal cell carcinoma and breast cancer. Future studies are needed to identify the patients most likely to benefit from this form of therapy, and to define its role in combination with chemotherapy, hormones and growth factor inhibitors.

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“…In vitro studies of the combination of RAD001 and the reversible erbB1 tryosine kinase inhibitor gefitinib suggested that the combination was associated with sequence-dependence synergism in cancer cell lines that were either sensitive or resistant to gefitinib, with the superior sequence demonstrated as gefitinib followed by RAD001 [96]. Simultaneous treatment produced additive activity.…”

Section: Rad001mentioning

confidence: 95%