MET inhibitor tepotinib antagonizes multidrug resistance mediated by ABCG2 transporter: In vitro and in vivo study

Wu, Zhuo‐Xun; Teng, Quincy; Yang, Yuqi; Acharekar, Nikita; Wang, Jingquan; He, Min; Yoganathan, Sabesan; Lin, Jun; Wang, Jian; Chen, Zhe‐Sheng

doi:10.1016/j.apsb.2021.12.018

Cited by 9 publications

(13 citation statements)

References 41 publications

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“…The spatial structure ceralasertib was constructed for docking simulation as previously described ( Wu et al, 2022 ). Human P-gp protein model 6QEX (paclitaxel bound) ( Alam et al, 2019 ) and BCRP protein model 6VXI (mitoxantrone bound) ( Jackson et al, 2018 ) were obtained from RCSB Protein Data Bank.…”

Section: Methodsmentioning

confidence: 99%

“…It is well-established that some tyrosine kinase inhibitors (TKIs) can interact with P-gp/BCRP and can be classified as functional modulators or transported substrates. On the one hand, studies showed that tepotinib ( Wu et al, 2022 ), poziotinib ( Zhang et al, 2020 ) and lazertinib ( Fan et al, 2022 ) are able to inhibit the function of P-gp and BCRP in cancer cells, thus mitigating MDR in combination treatment. On the other hand, the pharmacokinetics of frontline TKIs, for example, imatinib ( Park et al, 2021 ) and gefitinib ( Agarwal et al, 2010 ), are affected by P-gp/BCRP.…”

Section: Introductionmentioning

confidence: 99%

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Multidrug resistance transporters P-gp and BCRP limit the efficacy of ATR inhibitor ceralasertib in cancer cells

Chen,

Wu,

Wang

et al. 2024

Front. Pharmacol.

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The therapeutic effect of chemotherapy and targeted therapy are known to be limited by drug resistance. Substantial evidence has shown that ATP-binding cassette (ABC) transporters P-gp and BCRP are significant contributors to multidrug resistance (MDR) in cancer cells. In this study, we demonstrated that a clinical-staged ATR inhibitor ceralasertib is susceptible to P-gp and BCRP-mediated MDR. The drug resistant cancer cells were less sensitive to ceralasertib compared to the parental cells. Moreover, ceralasertib resistance can be reversed by inhibiting the drug efflux activity of P-gp and BCRP. Interestingly, ceralasertib was able to downregulate the level of P-gp but not BCRP, suggesting a potential regulation between ATR signaling and P-gp expression. Furthermore, computational docking analysis predicted high affinities between ceralasertib and the drug-binding sites of P-gp and BCRP. In summary, overexpression of P-gp and BCRP are sufficient to confer cancer cells resistance to ceralasertib, underscoring their role as biomarkers for therapeutic efficacy.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Multidrug resistance transporters P-gp and BCRP limit the efficacy of ATR inhibitor ceralasertib in cancer cells

Chen,

Wu,

Wang

et al. 2024

Front. Pharmacol.

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“…The third generation, exampled by tariquidar and zosuquidar, is able to overcome the selectivity problem; however, the performance in clinical settings turns out to be unsuccessful due to interpatient variability 127 . In the recent decade, some repurposing targeted anticancer drugs, such as selonsertib, tepotinib, and poziotinib, have been discovered as dual inhibitors for ABCB1 and ABCG2 128–130 . Inhibitors that can antagonize both ABCB1‐ and ABCC1‐mediated resistance have also been reported, exampled by cediranib and CBT‐1 (tetrandrine) 131,132 .…”

Section: Resistance Mechanisms In Cancer and Combating Strategiesmentioning

confidence: 99%

“…Targeted anticancer drugs, such as tepotinib and poziotinib, could inhibit ABCB1 and ABCG2 to reverse the resistance to ABCB1 and ABCG2 substrates [128][129][130] Mutation of drug targets Development of new generation or multitarget anticancer drug EAI045 is the first allosteric EGFR TKI designed to overcome the acquired resistance mediated by T790M and C797S mutations 147 DNA damage repair Combination with DNA repair inhibitor ERK or p38 kinase inhibitors could overcome the resistance mediated by 5-FU-induced ERCC1 overexpression 198…”

Section: Drug Inactivation Drug Replacement or Combination With Enzym...mentioning

confidence: 99%

“… 127 In the recent decade, some repurposing targeted anticancer drugs, such as selonsertib, tepotinib, and poziotinib, have been discovered as dual inhibitors for ABCB1 and ABCG2. 128 , 129 , 130 Inhibitors that can antagonize both ABCB1‐ and ABCC1‐mediated resistance have also been reported, exampled by cediranib and CBT‐1 (tetrandrine). 131 , 132 Targeting multiple ABC transporters may be more prospective given that co‐expression of different ABC transporters is common in tumor tissues and multitargeting drugs may be beneficial to avoid compensatory upregulation of another transporter induced by selective inhibition of a single transporter.…”

Section: Resistance Mechanisms In Cancer and Combating Strategiesmentioning

confidence: 99%

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Understanding and targeting resistance mechanisms in cancer

Lei

Teng

Wurpel

et al. 2023

MedComm

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Resistance to cancer therapies has been a commonly observed phenomenon in clinical practice, which is one of the major causes of treatment failure and poor patient survival. The reduced responsiveness of cancer cells is a multifaceted phenomenon that can arise from genetic, epigenetic, and microenvironmental factors. Various mechanisms have been discovered and extensively studied, including drug inactivation, reduced intracellular drug accumulation by reduced uptake or increased efflux, drug target alteration, activation of compensatory pathways for cell survival, regulation of DNA repair and cell death, tumor plasticity, and the regulation from tumor microenvironments (TMEs). To overcome cancer resistance, a variety of strategies have been proposed, which are designed to enhance the effectiveness of cancer treatment or reduce drug resistance. These include identifying biomarkers that can predict drug response and resistance, identifying new targets, developing new targeted drugs, combination therapies targeting multiple signaling pathways, and modulating the TME. The present article focuses on the different mechanisms of drug resistance in cancer and the corresponding tackling approaches with recent updates. Perspectives on polytherapy targeting multiple resistance mechanisms, novel nanoparticle delivery systems, and advanced drug design tools for overcoming resistance are also reviewed.

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c-MET tyrosine kinase inhibitors reverse drug resistance mediated by the ATP-binding cassette transporter B1 (ABCB1) in cancer cells

Nazari,

Poustforoosh,

Paul

et al. 2024

3 Biotech

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MET inhibitor tepotinib antagonizes multidrug resistance mediated by ABCG2 transporter: In vitro and in vivo study

Cited by 9 publications

References 41 publications

Multidrug resistance transporters P-gp and BCRP limit the efficacy of ATR inhibitor ceralasertib in cancer cells

Multidrug resistance transporters P-gp and BCRP limit the efficacy of ATR inhibitor ceralasertib in cancer cells

Understanding and targeting resistance mechanisms in cancer

c-MET tyrosine kinase inhibitors reverse drug resistance mediated by the ATP-binding cassette transporter B1 (ABCB1) in cancer cells

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