Overexpression of ABCB1 and ABCG2 contributes to reduced efficacy of the PI3K/mTOR inhibitor samotolisib (LY3023414) in cancer cell lines

Wu, Chung-Pu; Hung, Cheng-Yu; Lusvarghi, Sabrina; Huang, Yang-Hui; Tseng, Pin-Jung; Hung, Tai‐Ho; Yu, Jau‐Song; Ambudkar, Suresh V.

doi:10.1016/j.bcp.2020.114137

Cited by 21 publications

(24 citation statements)

References 102 publications

(123 reference statements)

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“…Learning that MLN7243 is an ABCG2 substrate, the in silico docking analysis was performed using the recently reported cryo-EM structures of human ABCG2. The predicted docking score was −9.553 kcal/mol, which is similar to other substrates such as OTS964 ( Yang et al, 2021 ) and samotolisib ( Wu et al, 2020a ). Hence, the result indicates that MLN7243 may interact with ABCG2 in the substrate-binding site.…”

Section: Discussionsupporting

confidence: 63%

Overexpression of ABCG2 Confers Resistance to MLN7243, a Ubiquitin-Activating Enzyme (UAE) Inhibitor

Yang

Wang

et al. 2021

Front. Cell Dev. Biol.

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Overexpression of ATP-binding cassette transporter superfamily G member 2 (ABCG2), is known as a major mechanism mediating multidrug resistance (MDR) in cancer cells. MLN7243 is a small-molecule ubiquitin activating enzyme inhibitor currently under clinical investigation. The aim of the current study is to determine if MLN7243 is a substrate of MDR-related ABCG2 transporter. Our results showed that cancer cells overexpressing ABCG2 transporter were resistant to MLN7243 compared to the parental cells, while knockout of ABCG2 gene or pharmacological inhibition of ABCG2 efflux function completely reversed the drug resistance. Unexpectedly, the endogenous low expression of ABCG2 is sufficient to confer cancer cells resistance to MLN7243. The ABCG2 ATPase assay and HPLC assay suggested that MLN7243 can significantly stimulate ABCG2 ATPase activity and be pumped out from ABCG2-overexpressing cells by ABCG2. The docking analysis also implied that MLN7243 binds to ABCG2 drug-binding pocket with optimal binding affinity. However, MLN7243 did not competitively inhibit the efflux of other ABCG2 substrate drugs, indicating it may not serve as an MDR reversal agent. In conclusion, our study provides direct in vitro evidence to show that MLN7243 is a potent ABCG2 substrate. If our results can be translated to humans, it suggests that combining MLN7243 with ABCG2 inhibitors may enhance the anticancer efficacy for patients with high tumor ABCG2 level.

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Section: Discussionsupporting

confidence: 63%

Overexpression of ABCG2 Confers Resistance to MLN7243, a Ubiquitin-Activating Enzyme (UAE) Inhibitor

Yang

Wang

et al. 2021

Front. Cell Dev. Biol.

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“…Samotolisib/LY3023414 is a dual inhibitor of PI3Kα and mTOR with potential anti-neoplastic activity [ 386 ]. A phase I trial evaluated the safety of Samotolisib in patients with advanced solid tumors [ 387 ].…”

Section: Dual Pi3k/mtor Inhibitorsmentioning

confidence: 99%

PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects

Mishra

Patel

Alanazi

et al. 2021

IJMS

172

105

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The phospatidylinositol-3 kinase (PI3K) pathway is a crucial intracellular signaling pathway which is mutated or amplified in a wide variety of cancers including breast, gastric, ovarian, colorectal, prostate, glioblastoma and endometrial cancers. PI3K signaling plays an important role in cancer cell survival, angiogenesis and metastasis, making it a promising therapeutic target. There are several ongoing and completed clinical trials involving PI3K inhibitors (pan, isoform-specific and dual PI3K/mTOR) with the goal to find efficient PI3K inhibitors that could overcome resistance to current therapies. This review focuses on the current landscape of various PI3K inhibitors either as monotherapy or in combination therapies and the treatment outcomes involved in various phases of clinical trials in different cancer types. There is a discussion of the drug-related toxicities, challenges associated with these PI3K inhibitors and the adverse events leading to treatment failure. In addition, novel PI3K drugs that have potential to be translated in the clinic are highlighted.

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“…Specific hydrophobic and aromatic interactions between citarinostat and nearby residues in the pocket were identified. The binding energy score suggests a strong affinity of citarinostat for both transporters similar to other modulators (refs [ 56 , 57 ]). Collectively, the results of this study support the conclusion that citarinostat is a substrate for both ABCB1 and ABCG2.…”

Section: Discussionmentioning

confidence: 76%

“…One of the most probable explanations for reduced drug efficacy in ABCB1- and ABCG2-overexpressing multidrug-resistant cancer cells is the reduced intracellular drug accumulation caused by ABCB1- and ABCG2-mediated drug efflux [ 34 ]. To this end, we treated KB-3-1, KB-V-1, S1, and S1-M1-80 cells with citarinostat in the presence or absence of tariquidar or Ko143 and determined the intracellular concentration of citarinostat in these cells using a liquid chromatography/tandem mass spectrometry (LC-MS/MS) method as described previously [ 56 , 57 ] ( Figure 4 A). We found that the reduced intracellular accumulation of citarinostat in KB-V-1 and S1-M1-80 cancer cells ( Figure 4 B) was significantly restored by tariquidar and Ko143, signifying that the activity of ABCB1 and ABCG2 contributes greatly to the reduced efficacy of citarinostat in these cancer cells.…”

Section: Resultsmentioning

confidence: 99%

Overexpression of Human ABCB1 and ABCG2 Reduces the Susceptibility of Cancer Cells to the Histone Deacetylase 6-Specific Inhibitor Citarinostat

Hung

Lusvarghi

et al. 2021

IJMS

Self Cite

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Citarinostat (ACY-241) is a promising oral histone deacetylase 6 (HDAC6)-selective inhibitor currently in clinical trials for the treatment of multiple myeloma (MM) and non-small-cell lung cancer (NSCLC). However, the inevitable emergence of resistance to citarinostat may reduce its clinical effectiveness in cancer patients and limit its clinical usefulness in the future. In this study, we investigated the potential role of the multidrug efflux transporters ABCB1 and ABCG2, which are two of the most common mechanisms of acquired resistance to anticancer drugs, on the efficacy of citarinostat in human cancer cells. We discovered that the overexpression of ABCB1 or ABCG2 significantly reduced the sensitivity of human cancer cells to citarinostat. We demonstrated that the intracellular accumulation of citarinostat and its activity against HDAC6 were substantially reduced by the drug transport function of ABCB1 and ABCG2, which could be restored by treatment with an established inhibitor of ABCB1 or ABCG2, respectively. In conclusion, our results revealed a novel mechanism by which ABCB1 and ABCG2 actively transport citarinostat away from targeting HDAC6 in cancer cells. Our results suggest that the co-administration of citarinostat with a non-toxic modulator of ABCB1 and ABCG2 may optimize its therapeutic application in the clinic.

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Overexpression of ABCB1 and ABCG2 contributes to reduced efficacy of the PI3K/mTOR inhibitor samotolisib (LY3023414) in cancer cell lines

Cited by 21 publications

References 102 publications

Overexpression of ABCG2 Confers Resistance to MLN7243, a Ubiquitin-Activating Enzyme (UAE) Inhibitor

Overexpression of ABCG2 Confers Resistance to MLN7243, a Ubiquitin-Activating Enzyme (UAE) Inhibitor

PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects

Overexpression of Human ABCB1 and ABCG2 Reduces the Susceptibility of Cancer Cells to the Histone Deacetylase 6-Specific Inhibitor Citarinostat

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