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rociletinib(CO-1686) enhanced the efficacy of chemotherapeutic agents in ABCG2-overexpressing cancer cells in vitro and in vivo

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Acta Pharmaceutica Sinica B 2020年第5期10卷 799-811页

作者： Fanpu Zeng Fang Wang Zongheng Zheng Zhen Chen Kenneth Kin Wah To Hong Zhang Qian Han Liwu Fu The Third Affiliated Hospital of Sun Yat-sen University Guangzhou 510000China State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteSun Yat-sen University Cancer CenterGuangzhou 510060China School of Pharmacy Faculty of Medicinethe Chinese University of Hong KongHong KongSARChina Guangzhou Handy Biotechnological Co. Ltd.Guangzhou 511400China

Overexpression of adenosine triphosphate(ATP)-binding cassette subfamily G member 2(ABCG2)in cancer cells is known to cause multidrug resistance(MDR),which severely limits the clinical efficacy of ***,there is no FDA-approved MDR modulator for clinical *** this study,rociletinib(CO-1686),a mutant-selective epidermal growth factor receptor(EGFR)tyrosine kinase inhibitor(TKI),was found to significantly improve the efficacy of ABCG2 substrate chemotherapeutic agents in the transporter-overexpressing cancer cells in vitro and in MDR tumor xenografts in nude mice,without incurring additional *** studies revealed that in ABCG2-overexpressing cancer cells,rociletinib inhibited ABCG2-mediated drug efflux and increased intracellular accumulation of ABCG2 probe ***,rociletinib,inhibited the ATPase activity,and competed with[125I]iodoarylazidoprazosin(IAAP)photolabeling of ***,ABCG2 expression at mRNA and protein levels was not altered in the ABCG2-overexpressing cells after treatment with *** addition,rociletinib did not inhibit EGFR downstream signaling and phosphorylation of protein kinase B(AKT)and extracellular signal-regulated kinase(ERK).Our results collectively showed that rociletinib reversed ABCG2-mediated MDR by inhibiting ABCG2 efflux function,thus increasing the cellular accumulation of the transporter substrate anticancer *** findings advocated the combination use of rociletinib and other chemotherapeutic drugs in cancer patients with ABCG2-overexpressing MDR tumors.

关键词： rociletinib Tyrosine kinase inhibitor Multidrug resistance ABCG2 ATPase

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rociletinib(CO-1686) enhanced efficacy of chemotherapeutic agents in ABCG2-overexpressing cancer cells in vitro and in vivo

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中国药理学与毒理学杂志 2019年第10期 891-892页

作者： ZENG Fan-pu WANG Fang ZHENG Zong-heng CHEN Zhen Kenneth Kin Wah To ZHANG Hong HAN Qian FU Li-wu State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Guangdong Esophageal Cancer Institute Sun Yat-Sen University Cancer Center

The abnormal expression and function of ATP-binding cassette subfamily G member 2(ABCG2) is correlated with development of multidrug resistance(MDR), and lead to lower response to ***, there is no FDA-approved commercial MDR modulator for clinical use. Here, We found rociletinib(CO-1686), a mutant-selective epidermal growth factor receptor(EGFR) tyrosine kinase inhibitor(TKI), significantly improved the efficacy of substrate chemotherapeutic agents in ABCG2-overexpressing cancer cells and also in ABCG2-overexpressing S1-MI-80 cell xenografts in nude mice, without incurring additional toxicity. Mechanistic studies revealed that in ABCG2-overexpressing cancer cells, rociletinib inhibited ABCG2-mediated drug efflux, and increased intracellular accumulation of ABCG2 probe substrates. Moreover, rociletinib, inhibited the ATPase activity, and competed with [125 I] iodoarylazidoprazosin(IAAP) photolabeling of ABCG2. The expression of ABCG2 at protein and m RNA levels was not altered when ABCG2-overexpressing cells were treated with rociletinib. In addition, rociletinib did not inhibit Erb B downstream signaling of AKT and ERK and their phosphorylations. The all results showed that rociletinib increased the accumulation of substrates in cells by inhibiting the efflux function of ABCG2, and reversed ABCG2-related MDR. Therefore, rociletinib might be useful in developing combination chemotherapy in the patients with ABCG2-overexpressing MDR tumors.

关键词： rociletinib combination chemotherapy chemotherapeutic agents

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Resistance to epidermal growth factor receptor inhibition in non-small cell lung cancer

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Cancer Drug Resistance 2018年第4期1卷 230-249页

作者： Nele Van Der Steen Elisa Giovannetti Daniela Carbone Alessandro Leonetti Christian D.Rolfo Godefridus J.Peters Department of Medical Oncology VU University Medical CenterAmsterdam 1081 HVthe Netherlands Department of Pathology Antwerp University HospitalAntwerp 2650Belgium Center for Oncological Research University of AntwerpAntwerp 2610Belgium Cancer Pharmacology Lab AIRC Start-Up UnitUniversity of PisaPisa 56124Italy Medical Oncology Unit University Hospital of ParmaParma 43126Italy University of Maryland Greenebaum Comprehensive Cancer Center Baltimore21220 MDUSA

Aberrant activation of the epidermal growth factor receptor(EGFR)is a driving force for cancer growth in a subgroup of non-small cell lung cancer *** patients can be identified by the presence of activating EGFR *** three generations of EGFR-tyrosine kinase inhibitors(TKIs)have been approved by the Food and Drug Administration and European Medicine *** paper reviews the structure of EGFR and the downstream signaling pathways of EGFR and describes the mechanisms of intrinsic and acquired resistance against *** mechanisms include secondary or tertiary mutations in EGFR,the activation of bypassing signaling pathways or a histological transformation to small cell lung ***,drug efflux transporters will affect the cellular accumulation of EGFR-TKIs and penetration of the first generation of EGFR-TKI into the *** sequestration of some EGFR-TKIs may also prevent the drugs to reach their *** conclusion,resistance to EGFR-TKIs is multifactorial,including primary and acquired mutations in the EGFR gene,activation of bypassing pathways and limited uptake of drugs in the cells or target *** pharmacological studies are needed in order to develop new specific compounds targeted to overcome new resistance mechanisms in order to enable a personalized treatment approach.

关键词： Epidermal growth factor receptor non-small cell lung cancer resistance EGFR-tyrosine kinase inhibitors erlotinib gefitinib afatinib osimertinib rociletinib

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