Targeting Oncogene mRNA Translation in B-Cell Malignancies with eFT226, a Potent and Selective Inhibitor of eIF4A

Thompson, P.; Eam, Boreth; Young, Nathan P.; Fish, Sarah; Chen, Joan; Barrera, Maria; Howard, Haleigh; Sung, Eric; Parra, Ana; Staunton, Jocelyn; Chiang, Gary G.; Gerson-Gurwitz, Adina; Wegerski, Christopher J.; Nevarez, Andres; Clarine, Jeff; Sperry, Samuel; Xiang, Alan X.; Nilewski, Christian; Packard, Garrick K.; Michels, Theodore; Tran, Chinh; Sprengeler, Paul A.; Ernst, Justin T.; Reich, Siegfried; Webster, Kevin R.

doi:10.1158/1535-7163.mct-19-0973

Cited by 37 publications

(31 citation statements)

References 33 publications

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“…Several mechanisms, including activation of oncogenes, mutation of antioncogene, and dysregulation of cancer-associated signaling pathway, are involved in chemoresistance [3][4][5]. N6-methyladenosine (m6A) modification is one of the most prevalent mRNA modification and influences mRNA transcription, stabilization, and translation [6].…”

Section: Introductionmentioning

confidence: 99%

ALKBH5-HOXA10 loop-mediated JAK2 m6A demethylation and cisplatin resistance in epithelial ovarian cancer

Nie

Zhang

Liu

et al. 2021

J Exp Clin Cancer Res

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Background Chemotherapy resistance remains a barrier to improving the prognosis of epithelial ovarian cancer (EOC). ALKBH5 has recently been shown to be one of the RNA N6-methyladenosine (m6A) demethyltransferases associated with various cancers, but its role in cancer therapeutic resistance remains unclear. This study aimed to investigate the role of AlkB homolog 5 (ALKBH5) in cisplatin-resistant EOC. Methods Functional assays were performed both in vitro and in vivo. RNA sequencing (RNA-seq), m6A-modified RNA immunoprecipitation sequencing (MeRIP-seq), chromatin immunoprecipitation, RNA immunoprecipitation, and luciferase reporter and actinomycin-D assays were performed to investigate RNA/RNA interaction and m6A modification of the ALKBH5-HOXA10 loop. Results ALKBH5 was upregulated in cisplatin-resistant EOC and promoted cancer cell cisplatin resistance both in vivo and in vitro. Notably, HOXA10 formed a loop with ALKBH5 and was found to be the upstream transcription factor of ALKBH5. HOXA10 overexpression also facilitated EOC cell chemoresistance both in vivo and in vitro. Collective results of MeRIP-seq and RNA-seq showed that JAK2 is the m6A-modified gene targeted by ALKBH5. The JAK2/STAT3 signaling pathway was activated by overexpression of the ALKBH5-HOXA10 loop, resulting in EOC chemoresistance. Cell sensitivity to cisplatin was rescued by ALKBH5 and HOXA10 knockdown or inhibition of the JAK2/STAT3 signaling pathway in EOC cells overexpressing ALKBH5-HOXA10. Conclusions The ALKBH5-HOXA10 loop jointly activates the JAK2/STAT3 signaling pathway by mediating JAK2 m6A demethylation, promoting EOC resistance to cisplatin. Thus, inhibition of the expression of the ALKBH5-HOXA10 loop may be a potential strategy to overcome cisplatin resistance in EOC.

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Section: Introductionmentioning

confidence: 99%

ALKBH5-HOXA10 loop-mediated JAK2 m6A demethylation and cisplatin resistance in epithelial ovarian cancer

Nie

Zhang

Liu

et al. 2021

J Exp Clin Cancer Res

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“…In particular, rocaglates ( Bordeleau et al, 2008 ; Novac et al, 2004 ) demonstrate anti-cancer potency in vitro and in vivo ( Alachkar et al, 2013 ; Bordeleau et al, 2008 ; Kogure et al, 2013 ; Lucas et al, 2009 ; Manier et al, 2017 ; Novac et al, 2004 ; Saradhi et al, 2011 ) and are also effective against parasitic ( Langlais et al, 2018 ), fungal ( Iyer et al, 2020 ), and viral ( Gordon et al, 2020 ; Müller et al, 2020 ; Todt et al, 2018 ) infections, including SARS-CoV-2 ( Gordon et al, 2020 ; Mani et al, 2020 ). Zotatifin/eFT226 ( Ernst et al, 2020 ; Thompson et al, 2021 ) recently became the first rocaglate to enter use in humans, entering clinical evaluation for advanced solid tumors ( ClinicalTrials.gov : NCT04092673 ) and COVID-19 ( ClinicalTrials.gov : NCT04632381 ). These endeavors are premised solely on the understanding of these compounds as disruptors of eIF4A activity ( Chan et al, 2019 ; Chu et al, 2020 ; Gandin et al, 2016 ; Iwasaki et al, 2016 ; Iwasaki et al, 2019 ; Rubio et al, 2014 ; Thompson et al, 2021 ; Wolfe et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Proteomics reveal cap-dependent translation inhibitors remodel the translation machinery and translatome

Cunningham

Manara

et al. 2021

Cell Reports

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“…The derivative DMDAPatA induced apoptosis of CLL cells and synergized with ABT-199 to enhance cell killing. Recently, eFFECTOR Therapeutics’ new compound, eFT226, was shown to selectively inhibit translation of eIF4A selective genes that was dependent on the presence of the 5ʹ-UTR sequences for selectivity [ 46 ]. eFT226 also caused a G1 cell cycle arrest in lymphoma cell lines due to the inhibition of translation of MYC, CDK4 and cyclin D1, which led to anti-tumor activity in vivo [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, eFFECTOR Therapeutics’ new compound, eFT226, was shown to selectively inhibit translation of eIF4A selective genes that was dependent on the presence of the 5ʹ-UTR sequences for selectivity [ 46 ]. eFT226 also caused a G1 cell cycle arrest in lymphoma cell lines due to the inhibition of translation of MYC, CDK4 and cyclin D1, which led to anti-tumor activity in vivo [ 46 ]. Overall, our study demonstrates that eIF4Ai can deprive CLL cells of both pro-proliferation and pro-survival effectors following BCR activation and may be an effective therapeutic strategy for B-cell malignancies.…”

Section: Discussionmentioning

confidence: 99%

Targeted inhibition of eIF4A suppresses B-cell receptor-induced translation and expression of MYC and MCL1 in chronic lymphocytic leukemia cells

Wilmore

Rogers‐Broadway

Taylor

et al. 2021

Cell. Mol. Life Sci.

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Signaling via the B-cell receptor (BCR) is a key driver and therapeutic target in chronic lymphocytic leukemia (CLL). BCR stimulation of CLL cells induces expression of eIF4A, an initiation factor important for translation of multiple oncoproteins, and reduces expression of PDCD4, a natural inhibitor of eIF4A, suggesting that eIF4A may be a critical nexus controlling protein expression downstream of the BCR in these cells. We, therefore, investigated the effect of eIF4A inhibitors (eIF4Ai) on BCR-induced responses. We demonstrated that eIF4Ai (silvestrol and rocaglamide A) reduced anti-IgM-induced global mRNA translation in CLL cells and also inhibited accumulation of MYC and MCL1, key drivers of proliferation and survival, respectively, without effects on upstream signaling responses (ERK1/2 and AKT phosphorylation). Analysis of normal naïve and non-switched memory B cells, likely counterparts of the two main subsets of CLL, demonstrated that basal RNA translation was higher in memory B cells, but was similarly increased and susceptible to eIF4Ai-mediated inhibition in both. We probed the fate of MYC mRNA in eIF4Ai-treated CLL cells and found that eIF4Ai caused a profound accumulation of MYC mRNA in anti-IgM treated cells. This was mediated by MYC mRNA stabilization and was not observed for MCL1 mRNA. Following drug wash-out, MYC mRNA levels declined but without substantial MYC protein accumulation, indicating that stabilized MYC mRNA remained blocked from translation. In conclusion, BCR-induced regulation of eIF4A may be a critical signal-dependent nexus for therapeutic attack in CLL and other B-cell malignancies, especially those dependent on MYC and/or MCL1.

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Targeting Oncogene mRNA Translation in B-Cell Malignancies with eFT226, a Potent and Selective Inhibitor of eIF4A

Abstract: KRW were employees and shareholders when the studies were performed.

Cited by 37 publications

References 33 publications

ALKBH5-HOXA10 loop-mediated JAK2 m6A demethylation and cisplatin resistance in epithelial ovarian cancer

ALKBH5-HOXA10 loop-mediated JAK2 m6A demethylation and cisplatin resistance in epithelial ovarian cancer

Proteomics reveal cap-dependent translation inhibitors remodel the translation machinery and translatome

Targeted inhibition of eIF4A suppresses B-cell receptor-induced translation and expression of MYC and MCL1 in chronic lymphocytic leukemia cells

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