Effect of re-treatment with gefitinib (‘Iressa’, ZD1839) after acquisition of resistance

Kurata, Takeshi; Tamura, Kazuo; Kaneda, Hiroyasu; Nogami, T.; Uejima, Hisao; Asai, G.; Nakagawa, Kazuhiko; Fukuoka, Masahiro

doi:10.1093/annonc/mdh006

Cited by 94 publications

(73 citation statements)

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“…Of interest, after the development of acquired resistance to gefitinib, the lung cancer patients in these reports regained sensitivity to gefitinib after a several month gefitinib-free interval. [21][22][23][24] Similar effect was observed in this RCC cohort in regards to a greater time off prior sunitinib associated with a better response, but response to prior sunitinib did not appear to impact response at rechallenge within the limitations of this small study.…”

Section: Discussionsupporting

confidence: 55%

Sunitinib rechallenge in metastatic renal cell carcinoma patients

Zama

Hutson

Elson

et al. 2010

Cancer

123

100

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BACKGROUND: Sunitinib was a standard initial therapy in metastatic renal cell carcinoma (mRCC). Given the fact that many patients progressed through many available therapies and antitumor activity had been demonstrated with sequential vascular endothelial growth factor-targeting approaches, a retrospective review was performed of the experience of rechallenge with sunitinib in sunitinib-refractory mRCC. METHODS: mRCC patients who received sunitinib therapy after disease progression on prior sunitinib and other therapy were retrospectively identified. Patient characteristics, toxicity, clinical outcome, Response Evaluation Criteria in Solid Tumors (RECIST) objective response rate, and progression-free survival (PFS) were recorded. RESULTS: Twenty-three mRCC patients who were rechallenged with sunitinib were identified. Upon rechallenge, 5 patients (22%) achieved an objective partial response. The median PFS with initial treatment was 13.7 months and 7.2 months with rechallenge. Patients with >6-month interval between sunitinib treatments had a longer PFS with rechallenge than patients who started the rechallenge within 6 months (median PFS, 16.5 vs 6.0 months; P ¼ .03). There was no significant difference in outcome to sunitinib rechallenge based on number or mechanism of intervening treatments. Substantial new toxicity or significantly increased severity of prior toxicity was not seen during rechallenge in this cohort. CONCLUSIONS: Sunitinib rechallenge had potential benefits and was tolerated in select metastatic RCC patients. Additional prospective investigation was warranted.

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Section: Discussionsupporting

confidence: 55%

Sunitinib rechallenge in metastatic renal cell carcinoma patients

Zama

Hutson

Elson

et al. 2010

Cancer

123

100

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“…[25][26][27] It has been reported that some patients in whom treatment with gefitinib is effective at first, ultimately become refractory. 30 Resistance is likely to remain a hurdle that limits the long-term effectiveness of TBT. PC-9 had a deletion mutation within the kinase domain of EGFR and is highly sensitive.…”

Section: Discussionmentioning

confidence: 99%

Establishment of a human non‐small cell lung cancer cell line resistant to gefitinib

Koizumi

Shimoyama²,

Taguchi³

et al. 2005

Intl Journal of Cancer

125

101

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The epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor gefitinib (Iressa 1 , ZD1839) has shown promising activity preclinically and clinically. Because comparative investigations of drug-resistant sublines with their parental cells are useful approaches to identifying the mechanism of gefitinib resistance and select factors that determine sensitivity to gefitinib, we established a human non-small cell lung carcinoma subline (PC-9/ZD) that is resistant to gefitinib. PC-9/ZD cells are $180-fold more resistant to gefitinib than their parental PC-9 cells and PC-9/ZD cells do not exhibit cross-resistance to conventional anticancer agents or other tyrosine kinase inhibitors, except AG-1478, a specific inhibitor of EGFR. PC-9/ZD cells also display significant resistance to gefitinib in a tumor-bearing animal model. To elucidate the mechanism of resistance, we characterized PC-9/ZD cells. The basal level of EGFR in PC-9 and PC-9/ZD cells was comparable. A deletion mutation was identified within the kinase domain of EGFR in both PC-9 and PC-9/ZD, but no difference in the sequence of EGFR cDNA was detected in either cell line. Increased EGFR/HER2 (and EGFR/HER3) heterodimer formations were demonstrated in PC-9/ ZD cells by chemical cross-linking and immunoprecipitation analysis in cells unexposed to gefitinib. Exposure to gefitinib increased heterodimer formation in PC-9 cells, but not in PC-9/ZD cells. Gefitinib inhibits EGFR autophosphorylation in a dose-dependent manner in PC-9 cells but not in PC-9/ZD cells. A marked difference in inhibition of site-specific phosphorylation of EGFR was observed at Tyr1068 compared to other tyrosine residues (Tyr845, 992 and 1045). To elucidate the downstream signaling in the PC9/ZD cellular machinery, complex formation between EGFR and its adaptor proteins GRB2, SOS, and Shc was examined. A marked reduction in the GRB2-EGFR complex and absence of SOS-EGFR were observed in PC-9/ZD cells, even though the protein levels of GRB2 and SOS in PC-9 and PC-9/ZD cells were comparable. Expression of phosphorylated AKT was increased in PC-9 cells and inhibited by 0.02 mM gefitinib. But the inhibition was not significant in PC-9/ ZD cells. These results suggest that alterations of adaptor-proteinmediated signal transduction from EGFR to AKT is a possible mechanism of the resistance to gefitinib in PC-9/ZD cells. These phenotypes including EGFR-SOS complex and heterodimer formation of HER family members are potential biomarkers for predicting resistance to gefitinib. ' 2005 Wiley-Liss, Inc.

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“…Small molecule tyrosine kinase inhibitors, such as Iressa/ZD1839/Gefitinib and GW572016, are another class of drugs targeting the EGF family receptors. However, it is not uncommon that resistance to these drugs develops after an initial response (14)(15)(16)(17) via diverse mechanisms (16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Microarray-Assisted Pathway Analysis Identifies Mitogen-Activated Protein Kinase Signaling as a Mediator of Resistance to the Green Tea Polyphenol Epigallocatechin 3-Gallate in Her-2/neu–Overexpressing Breast Cancer Cells

Guo

Lü²,

Subramanian³

et al. 2006

Cancer Research

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Overexpression of the epidermal growth factor receptor family member Her-2/neu in breast cancer leads to autophosphorylation of the receptor and induction of multiple downstream signaling pathways, including the Akt kinase to nuclear factor-nB (NF-nB) cascade that is associated with poor prognosis. Previously, we showed that the green tea polyphenol epigallocatechin 3-gallate (EGCG) inhibits growth of NF639 Her-2/neu-driven breast cancer cells via reducing receptor autophosphorylation and downstream Akt and NF-nB activities. Interestingly, upon prolonged culture in the presence of EGCG, cells resistant to the polyphenol could be isolated. Here, we report that resistant cells have lost tyrosine phosphorylation on the Her-2/neu receptor. Surprisingly, they displayed elevated NF-nB activity, and inhibition of this activity sensitized cells to EGCG. Data from microarray studies of the original and resistant NF639 populations of cells were subjected to Gene Set Enrichment Analysis pathway assessment, which revealed that the mitogen activated protein kinase (MAPK) pathway was activated in the resistant cells. Treatment of the resistant cells with the MAPK inhibitor U0216 reduced growth in soft agar and invasive phenotype, whereas the combination of EGCG and U0216 resulted in cells with a cobblestone epithelial phenotype. Thus, activation of the MAPK pathway mediates resistance to EGCG.

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Effect of re-treatment with gefitinib (‘Iressa’, ZD1839) after acquisition of resistance

Cited by 94 publications

References 1 publication

Sunitinib rechallenge in metastatic renal cell carcinoma patients

Sunitinib rechallenge in metastatic renal cell carcinoma patients

Establishment of a human non‐small cell lung cancer cell line resistant to gefitinib

Microarray-Assisted Pathway Analysis Identifies Mitogen-Activated Protein Kinase Signaling as a Mediator of Resistance to the Green Tea Polyphenol Epigallocatechin 3-Gallate in Her-2/neu–Overexpressing Breast Cancer Cells

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