Downregulated ABCG2 Enhances Sensitivity to Topoisomerase I Inhibitor in Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor-Resistant Non-small Cell Lung Cancer

Ohtsuka, Kouki; Ohnìshì, H.; Morii, Takeshi; Fujiwara, Masachika; Kishino, Tomonori; Ogura, Wataru; Chiba, Misaki; Matsushima, Satsuki; Goya, Tomoyuki; Watanabe, Takashi

doi:10.1097/jto.0b013e3181f0b6af

Cited by 10 publications

(9 citation statements)

References 27 publications

(40 reference statements)

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“…In regards to the failed combination therapy, we hypothesized that the possible reason may be that the chemotherapy drugs disturbed the cell membrane transport of gefitinib consequently resulting in failure. A previous study reported that one mechanism for resistance to EGFR-TKI is associated with the downregulation of ABCG2 expression (23). In the present study, the results did not demonstrate a decrease in the expression of ABCG2 following the combination therapy.…”

Section: Discussionsupporting

confidence: 44%

Induced IGF-1R activation contributes to gefitinib resistance following combined treatment with paclitaxel, cisplatin and gefitinib in A549 lung cancer cells

Chen

et al. 2014

Oncology Reports

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Abstract. Gefitinib demonstrates excellent performance in the treatment of lung adenocarcinoma patients; yet, there was no added benefit in combination with chemotherapy as reported in a phase III clinical trial. For exploring the mechanism of the failed combination therapy in lung cancer, in the present study, four therapy assessment groups, including a control group, a chemotherapy group [paclitaxel + cisplatin (TP)], a gefitinib monotherapy group (G) and a combination group [paclitaxel + cisplatin + gefitinib (TP+G)], were established in an A549 cell line and mouse xenotransplanted tumor models. By HPLC, we found that the gefitinib concentration was significantly higher in the combination group when compared to that in the G group in the non-small cell lung cancer cell line, A549 (p<0.05). Following the treatment time extension, an increased cell growth rate was observed in the combination group, while the cellular concentration of gefitinib was not decreased. The expression levels of P-IGF-1R, P-SRC and P-ERK in the fourth combination treatment group were significantly higher than levels in the fourth G treatment and control groups (p<0.05). Following downregulating of IGF-1R in the fourth combination treatment group, drug sensitivity was recovered in vitro. In the mouse model, compared with the gefitinib monotherapy group, the combination group exhibited a smaller tumor volume, lower body weight and reduced survival rate (p<0.05). Gefitinib concentrations in the serum and tumor tissues in the combination therapy group were also decreased when compared with these concentrations in the gefitinib alone group. The present study is the first to demonstrate that the decreased gefitinib concentration in serum and tumor tissues is one of the reasons resulting in the failed combination treatment (chemotherapy + gefitinib) in vivo study. Frequent use of the combination treatment in A549 lung cancer cells induced IGF-1R activation which contributed to gefitinib resistance and gave rise to the failure of the combination therapy. IntroductionLung cancer still remains the leading cause of cancer-related mortality in the world, and the majority of patients present with advanced disease at diagnosis or develop recurrence, neither of which is amenable to curative approaches (1). The epidermal growth factor receptor (EGFR) is expressed in a number of tumors, including non-small-cell lung cancer (NSCLC). EGFR is a member of the EGFR family that includes HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4) (2-4). Activation of the EGFR leads to receptor associated tyrosine kinase activity that initiates a cascade of events leading to downstream signaling and a variety of changes characteristic of malignant progression including upregulation of ras, raf, mitogen-activated phosphorylated (MAP) kinase, and phosphatidylinositol 3-kinase (PI3K) and the downstream protein-serine/threonine kinase Akt. In turn, cellular growth and invasive capacity are enhanced. Preclinical data indicate that small molecules that compete with adenosine triphos...

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Section: Discussionsupporting

confidence: 44%

Induced IGF-1R activation contributes to gefitinib resistance following combined treatment with paclitaxel, cisplatin and gefitinib in A549 lung cancer cells

Chen

et al. 2014

Oncology Reports

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“…In these studies, Akt-mediated translocation of EGFR to the nucleus was observed in the resistant cells, resulting in enhanced transcription of BCRP [254]. In contrast to these studies, the EGFR tyrosine kinase inhibitor AG1478 caused downregulation of BCRP expression in AG1478-resistant cells, along with collateral sensitivity to a topoisomerase I inhibiting agent, Hoechst 33342 [255]. …”

Section: Section 5 Recent Findings In Solid Tumorsmentioning

confidence: 99%

Role of breast cancer resistance protein (BCRP/ABCG2) in cancer drug resistance

Natarajan¹,

Xie²,

Baer³

et al. 2012

Biochemical Pharmacology

350

273

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Since cloning of the ATP-binding cassette (ABC) family member breast cancer resistance protein (BCRP/ABCG2) and its characterization as a multidrug resistance efflux transporter in 1998, BCRP has been the subject of more than two thousand scholarly articles. In normal tissues, BCRP functions as a defense mechanism against toxins and xenobiotics, with expression in the gut, bile canaliculi, placenta, blood-testis and blood-brain barriers facilitating excretion and limiting absorption of potentially toxic substrate molecules, including many cancer chemotherapeutic drugs. BCRP also plays a key role in heme and folate homeostasis, which may help normal cells survive under conditions of hypoxia. BCRP expression appears to be a characteristic of certain normal tissue stem cells termed “side population cells,” which are identified on flow cytometric analysis by their ability to exclude Hoechst 33342, a BCRP substrate fluorescent dye. Hence, BCRP expression may contribute to the natural resistance and longevity of these normal stem cells. Malignant tissues can exploit the properties of BCRP to survive hypoxia and to evade exposure to chemotherapeutic drugs. Evidence is mounting that many cancers display subpopulations of stem cells that are responsible for tumor self-renewal. Such stem cells frequently manifest the “side population” phenotype characterized by expression of BCRP and other ABC transporters. Along with other factors, these transporters may contribute to the inherent resistance of these neoplasms and their failure to be cured.

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“…The first mechanism involves data reported in a study by Ohtsuka et al (2010). Resistance to EGFR-TKI is associated with the downregulation of ABCG2 expression.…”

Section: Discussionmentioning

confidence: 99%

Phase I study of irinotecan and gefitinib in patients with gefitinib treatment failure for non-small cell lung cancer

et al. 2011

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Background:Currently, no effective treatments exist for non-small cell lung cancer (NSCLC) after failure of gefitinib therapy. Pre-clinical studies have demonstrated that gefitinib-resistant NSCLC cells are more sensitive to irinotecan than parental cells, and that combined administration of irinotecan and gefitinib has a synergistic additive effect. We conducted a phase I study to evaluate the combination of irinotecan and gefitinib as a therapeutic option for NSCLC patients with progressive disease (PD) after initial gefitinib treatment.Methods:Eligibility criteria included histologically confirmed NSCLC, age range of 20–74 years, refractory to or relapsed after gefitinib treatment, one or more previous chemotherapy regimens, Eastern Cooperative Oncology Group performance status 0–2, adequate organ function, and informed consent. Patients were treated with irinotecan on days 1 and 15, and treated daily with gefitinib from day 2 every 4 weeks. The treatment was continued until disease progression. The gefitinib dose was fixed at 250 mg. Irinotecan dosing started at 50 mg m−2 and was escalated in patients by 25 mg m−2 increments up to a maximum dose of 150 mg m−2.Results:Twenty-seven patients were enrolled: male/female=14/13; median age=60 (45–75); histology, adenocarcinoma/non-adenocarcinoma=25/2; performance status 0–1/2=19/8; previous response to gefitinib, partial response/stable disease/PD=21/2/4. Dose-limiting toxicities were observed in 2 patients at level 3. Maximum tolerated dose was not determined, and the full dose of irinotecan could be combined with the full dose of gefitinib. The disease control rate (DCR) and response rate (RR) were 69.2 and 26.9%, respectively. For 12 patients at level 5 (the recommended phase II dose), the DCR and RR were 75.0% and 41.7%, respectively. The median treatment cycles were 4; median time to treatment failure, 57 days (95% confidence interval (CI), 32–82 days); median overall survival, 244 days (95% CI, 185–303 days); and 1-year survival rate, 32.6%.Conclusion:The combination of irinotecan and gefitinib was well tolerated and potentially beneficial for NSCLC patients failing initial gefitinib monotherapy.

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Downregulated ABCG2 Enhances Sensitivity to Topoisomerase I Inhibitor in Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor-Resistant Non-small Cell Lung Cancer

Abstract: Resistance to EGFR TKI in NSCLC is associated with the downregulation of ABCG2 expression. A topoisomerase I inhibitor alone or in combination with EGFR TKI might offer a promising strategy for treating NSCLC that is resistant to EGFR TKI.

Cited by 10 publications

References 27 publications

Induced IGF-1R activation contributes to gefitinib resistance following combined treatment with paclitaxel, cisplatin and gefitinib in A549 lung cancer cells

Induced IGF-1R activation contributes to gefitinib resistance following combined treatment with paclitaxel, cisplatin and gefitinib in A549 lung cancer cells

Role of breast cancer resistance protein (BCRP/ABCG2) in cancer drug resistance

Phase I study of irinotecan and gefitinib in patients with gefitinib treatment failure for non-small cell lung cancer

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