Branched-Chain Amino Acid Metabolic Reprogramming Orchestrates Drug Resistance to EGFR Tyrosine Kinase Inhibitors

Wang, Yuetong; Zhang, Jian; Ren, Shengxiang; Sun, Dan; Huang, Hsin‐Yi; Wang, Hua; Jin, Yujuan; Li, Fuming; Zheng, Chao; Liu, Yang; Deng, Lei; Jiang, Zhenfei; Jiang, Tao; Han, Xiuxin; Hou, Shenda; Guo, Chenchen; Li, Fēi; Gao, Dong; Qin, Jun; Gao, Daming; Chen, Luonan; Wong, Kwok‐Kin; Li, Cheng; Hu, Liang; Zhou, Caicun; Ji, Hongbin

doi:10.1101/638007

Cited by 4 publications

(8 citation statements)

References 33 publications

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“…BCAT1 in particular is associated with cancer cell growth and has been proposed as a prognostic cell marker. 66,68,69 In addition, many studies have explored BCAT1 as a potential target for cancer therapeutics, as it is also linked to cell proliferation via m-Torc1 activity. 70 BCAA metabolism has been shown to alter gene expression in cancer cells by altering the epigenome.…”

Section: Discussionmentioning

confidence: 99%

A Transient Metabolic State In Melanoma Persister Cells Mediated By Chemotherapeutic Treatments

Karki

Angardi

Mier

et al. 2021

Preprint

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Persister cells are defined as the small fraction of quiescent cells in a bulk cancer cell population that can tolerate unusually high levels of drugs. Persistence is a transient state that poses an important health concern in cancer therapy. The mechanisms associated with persister phenotypes are highly diverse and complex, and many aspects of persister cell physiology remain to be explored. We applied a melanoma cell line and panel of chemotherapeutic agents to show that melanoma persister cells are not necessarily preexisting dormant cells or stem cells; in fact, they may be induced by cancer chemotherapeutics. Our metabolomics analysis and phenotype microarray assays further demonstrated that the levels of Krebs cycle molecules are significantly lower in the melanoma persister subpopulation than in the untreated bulk cell population due to increased utilization rates in persisters. Our data indicate that this observed metabolic remodeling is transient, as the consumption rates of Krebs cycle metabolites are significantly reduced in the progenies of persisters. Given that the mitochondrial electron transport chain (ETC) is more active in the persister subpopulation than in the bulk cancer cell population, we also verified that targeting ETC activity can reduce melanoma persistence. The reported metabolic remodeling feature seems to be a conserved characteristic of melanoma persistence, as it has been observed in various melanoma persister subpopulations derived from a diverse range of chemotherapeutics. Elucidating a global metabolic mechanism that contributes to persister survival and reversible switching will ultimately foster the development of novel cancer therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

A Transient Metabolic State In Melanoma Persister Cells Mediated By Chemotherapeutic Treatments

Karki

Angardi

Mier

et al. 2021

Preprint

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“…BCAT1 expression is confirmed to be associated with cancer progression in various solid tumors [4][5][6][7][8][9]27 , including cervical cancer 10 and HCC 12 . Increased BCAT1 expression correlates with the chemotherapeutic agent resistance 3,9,13 . For instance, Cho et al 3 reported that BCAT1 promoted IDH1 wild-type glioblastoma multiforme cell proliferation, invasion and increased resistance to bevacizumab treatment.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, Zhu et al 9 found that miR-218 increased chemosensitivity to cisplatin by targeting BCAT1 in prostate cancer. Moreover, Wang et al 13 showed that BCAT1 conferred sublethal tyrosine kinase inhibitor resistance in EGFR-mutated lung cancer cells through the H3K9 demethylation-mediated BCAA metabolism reprogramming. The above findings confirm the important role of BCAT1 in tumor drug resistance.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, BCAT1 decreased the cisplatin sensitivity of HCC cells 11 . Several studies also show that BCAT1 overexpression is associated with multi-drug resistance 3,9,13 , including bevacizumab on glioblastoma 3 , EGFR tyrosine kinase inhibitors on lung cancer 13 and cisplatin on prostate cancer 9 . However, the exact role and mechanism of the involvement of BCAT1 in cisplatin cytotoxicity remain undefined.…”

Section: Introductionmentioning

confidence: 99%

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BCAT1 decreases the sensitivity of cancer cells to cisplatin by regulating mTOR-mediated autophagy via branched-chain amino acid metabolism

et al. 2021

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Cisplatin is one of the most effective chemotherapy drugs and is widely used in the treatment of cancer, including hepatocellular carcinoma (HCC) and cervical cancer, but its therapeutic benefit is limited by the development of resistance. Our previous studies demonstrated that BCAT1 promoted cell proliferation and decreased cisplatin sensitivity in HCC cells. However, the exact role and mechanism of how BCAT1 is involved in cisplatin cytotoxicity remain undefined. In this study, we revealed that cisplatin triggered autophagy in cancer cells, with an increase in BCAT1 expression. The cisplatin-induced up-regulation of BCAT1 decreased the cisplatin sensitivity by regulating autophagy through the mTOR signaling pathway. In addition, branched-chain amino acids or leucine treatment inhibited cisplatin- or BCAT1-mediated autophagy and increased cisplatin sensitivity by activating mTOR signaling in cancer cells. Moreover, inhibition of autophagy by chloroquine increased cisplatin sensitivity in vivo. Also, the knockdown of BCAT1 or the administration of leucine activated mTOR signaling, inhibited autophagy, and increased cisplatin sensitivity in cancer cells in vivo. These findings demonstrate a new mechanism, revealing that BCAT1 decreases cisplatin sensitivity in cancer cells by inducing mTOR-mediated autophagy via branched-chain amino acid leucine metabolism, providing an attractive pharmacological target to improve the effectiveness of chemotherapy.

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“…3,5,9 Targeting drug-tolerant cancer cells and reversing their tolerance therefore provide a promising therapeutic opportunity to impede tumor relapse. 5,10,11 Proteasome inhibitors (PIs) have dramatically improved the treatment of multiple myeloma (MM) and other hematological malignancies, but relapses are frequent and acquired resistance to treatment eventually emerges. 12,13 Mixed-lineage leukemia (MLL), including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), is an aggressive hematologic malignancy with a poor prognosis.…”

Section: Introductionmentioning

confidence: 99%

Deubiquitinating Enzyme Inhibitor Alleviates Cyclin A1-mediated Proteasome Inhibitor Tolerance in Mixed-lineage Leukemia

Kang

et al. 2020

Preprint

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Background: Drug resistance is a significant obstacle to effective cancer treatment. Drug resistance develops from initially reversible drug-tolerant cancer cells, which offers therapeutic opportunities to impede cancer relapse. The mechanisms of resistance to proteasome inhibitor (PI) therapy have been investigated intensively; however, the ways by which drug-tolerant cancer cells orchestrate their adaptive responses to drug challenges remains largely unknown. Methods: RNA sequencing and bioinformatics analyses were employed to assess dysregulated cell cycle genes. Chromatin immunoprecipitation assays were performed to evaluate the involvement of MLL in cyclin A1 transcriptional activity. Cell cycle assays, cell viability assays, immunoblots, and apoptosis assays were performed to evaluate the dependency of cyclin A1 during tolerance acquisition.Results: Here, we demonstrated that cyclin A1 suppression elicited the development of transient PI tolerance in mixed-lineage leukemia (MLL) cells. This adaptive process involved reversible down-regulation of cyclin A1, which promoted PI resistance through cell cycle arrest. PI-tolerant MLL cells acquired cyclin A1 dependency, regulated directly by MLL protein. Loss of cyclin A1 function resulted in the emergence of drug tolerance, which was associated with patient relapse and reduced survival. Combination treatment with PI and deubiquitinating enzyme (DUB) inhibitors overcame this drug resistance by restoring cyclin A1 expression through chromatin crosstalk between histone H2B monoubiquitination and MLL-mediated histone H3 lysine 4 methylation. Conclusion: These results reveal the importance of cyclin A1-engaged cell cycle regulation in PI resistance in MLL cells, and suggest that cell cycle re-entry by DUB inhibitors may represent a promising epigenetic therapeutic strategy to prevent acquired drug resistance.

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Branched-Chain Amino Acid Metabolic Reprogramming Orchestrates Drug Resistance to EGFR Tyrosine Kinase Inhibitors

Cited by 4 publications

References 33 publications

A Transient Metabolic State In Melanoma Persister Cells Mediated By Chemotherapeutic Treatments

A Transient Metabolic State In Melanoma Persister Cells Mediated By Chemotherapeutic Treatments

BCAT1 decreases the sensitivity of cancer cells to cisplatin by regulating mTOR-mediated autophagy via branched-chain amino acid metabolism

Deubiquitinating Enzyme Inhibitor Alleviates Cyclin A1-mediated Proteasome Inhibitor Tolerance in Mixed-lineage Leukemia

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