Targeting Aurora B kinase prevents and overcomes resistance to EGFR inhibitors in lung cancer by enhancing BIM- and PUMA-mediated apoptosis

Tanaka, Kosuke; Yu, Helena A.; Yang, Suwen; Han, Song Iy; Selcuklu, S. Duygu; Kim, Kwanghee; Ramani, Shriram; Ganesan, Yogesh Tengarai; Moyer, Allison; Sinha, Shivam; Xie, Yuchen; Ishizawa, Kota; Osmanbeyoglu, Hatice U.; Lyu, Yang; Roper, Nitin; Guha, Udayan; Rudin, Charles M.; Kris, Mark G.; Hsieh, James J.; Cheng, Emily H.

doi:10.1016/j.ccell.2021.07.006

Cited by 89 publications

(60 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Once this balance is broken, it will lead to cancer. Recent studies showed apoptosis is the main way of cell death induced by various anticancer drugs ( Ball and Borthakur, 2020 ; Tanaka et al, 2021 ). All these suggest fucoidan may induce dysregulation of DNA replication and cell cycle, reduce cell adhesion, cause cell death in the form of apoptosis, to achieve the effect of anti-cancer ( Figure 6 ).…”

Section: Resultsmentioning

confidence: 99%

A Transcriptome Sequencing Study on Genome-Wide Gene Expression Differences of Lung Cancer Cells Modulated by Fucoidan

Zhao

Zhang

et al. 2022

Front. Bioeng. Biotechnol.

View full text Add to dashboard Cite

Fucoidan has received increasing attention in anti-(lung) tumors. However, the effect of fucoidan on the gene changes of lung cancer cells (LCCs) has not been examined systematically. Herein, we investigate the effect of fucoidan on the phenotypes of LCCs and their gene expression by transcriptome sequencing analysis. The phenotypes of LCCs are significantly inhibited by fucoidan. Importantly, compared to LCCs, 1 mg/ml fucoidan has no effect on the phenotypes of normal cells. Further, 6,930 differentially expressed genes (DEGs) in the transcriptome of LCCs (3,501 up-regulated and 3,429 down-regulated genes) are detected via RNA-sequencing between the fucoidan and control groups. Gene Ontology analysis confirms that DEGs are reflected in DNA replication, cell-substrate junction, regulation of cell cycle phase transition, apoptosis, focal adhesion, cadherin binding, and cell adhesion molecule binding. Thus, our findings on the transcriptomic level highlight the therapeutic potential of fucoidan for lung cancer treatment.

show abstract

Section: Resultsmentioning

confidence: 99%

A Transcriptome Sequencing Study on Genome-Wide Gene Expression Differences of Lung Cancer Cells Modulated by Fucoidan

Zhao

Zhang

et al. 2022

Front. Bioeng. Biotechnol.

View full text Add to dashboard Cite

show abstract

“…1D). In addition, apoptosis plays a crucial role in the response of cancer to EGFR TKIs 7 and also pemetrexed 27 . Our results showed that pro-apoptosis effect markedly enhanced post P-A sequence treatment, revealed by signi cantly increased expression of cleaved Caspase 3 and cleaved PARP1 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Emerging evidence reveals that the occurrence of resistance to third-generation EGFR TKIs is associated with long-term drug administration and coinstantaneous selection of pre-existing resistance clones as well as the evolution of drug-tolerant presisters 6,7 , accordingly upfront combination therapy based on different targets and mechanisms is promising to prevent and overcome the resistance to third-generation EGFR TKIs by enhancing tumor cytotoxicity and concomitantly reducing pre-existing resistance clones 8 . Several clinical trials, focusing third-generation EGFR TKIs-based combination therapy with immune checkpoint inhibitors (ICIs) and antiangiogenic therapy, were performed in recent years.…”

mentioning

confidence: 99%

Sequence-dependent synergistic effect of aumolertinib-pemetrexed combined therapy on EGFR-mutant non-small-cell lung carcinoma with pre-clinical and clinical evidence

Fang

Zhang

et al. 2022

Preprint

View full text Add to dashboard Cite

Background: Inevitably developed resistance of the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) limited its clinical benefit on non-small cell lung cancer (NSCLC). Upfront combination therapy is promising to prevent this resistance. Compelling clinical evidence indicated the failure of third-generation EGFR TKIs combined with either immunotherapy or antiangiogenic agents. In comparison, combined treatment of third-generation EGFR TKIs and chemotherapy might be a favorable choice. Herein, we systematically analyzed and compared the effects of pemetrexed and a novel third-generation EGFR TKI aumolertinib combined in different sequences, subsequently revealed the potential mechanisms and proved the optimal combination schedule with clinical retrospective study.Methods: Three combination schedules involving pemetrexed and aumolertinib in different sequences were developed. Their inhibition effects on cell proliferation and metastasis were firstly compared upon three human NSCLC cell lines in vitro, by cell counting kit-8, colony formation, wound healing and transwell assays respectively. Further evaluation in vivo was proceeded upon H1975 and HCC827 xenograft model. Gene and protein expression were detected by Q-PCR and western blot. Drug concentration was determined by LC-MS/MS. VEGF secretion was determined by ELISA. Tumor vessel was visualized by immunofluorescence. Lastly, a clinical retrospective study was raised with 65 patients’ data.Results: The combination of pemetrexed and aumolertinib exhibited a sequence-dependent and EGFR mutant-dependent synergistic effect in vitro and in vivo. Only treatment with aumolertinib following pemetrexed (P-A) exhibited synergistic effect with stronger anti-tumor growth and anti-metastasis ability than monotherapy and also other combination sequences. This synergism could exclusively be observed in H1975 and HCC827 but not A549. Pathway analysis showed that P-A significantly enhanced the suppression of EGFR pathway. In addition, our results intriguingly found an obvious reduction of VEGF secretion and the accompanying normalization of the intratumor vessel, consequently increasing intratumoral accumulation of pemetrexed in P-A group. Finally, the clinical retrospective study verified the synergistic effect of P-A combination by significantly superior tumor response than aumolertinib monotherapy.Conclusions: Aumolertinib-pemetrexed combined therapy is promising for EGFR mutant NSCLC but only in right administration sequence. P-A could become an advantageous combination strategy in clinical with synergistic inhibition of tumor growth and metastasis.

show abstract

“…Interestingly, the cells returned to spontaneous sensitivity after drug withdrawal ( 57 ). Subsequent studies identified other targets related to persister DT cells including IGF1-R ( 58 ), and Axl ( 59 ), in addition to modulation of apoptosis involving Mcl-1 ( 60 ) and Aurora kinases ( 61 ). In addition to this, sensitivity to 3rd G EGFR-TKIs had been restored in resistant cell lines generated after drug withdrawal ( 47 , 49 ), suggesting a non-genetic adaptation.…”

Section: Epigenetics In Egfr-tkis Resistance In Nsclcmentioning

confidence: 99%

“…Moreover, barasertib and tozasertib, a second AURK inhibitor, showed a significant antiproliferative effect on osimertinib-resistant cells with no observed difference in AURK expression level ( 33 ). Recently, the importance of AURK inhibition in enhancing BIM- and PUMA-mediated apoptosis upon EGFR-TKI therapy in EGFR-mutated lung cancer cells has been described ( 61 ). TPX2 expression was significantly increased in tumor tissue samples obtained from patients with advanced EGFR-mutant NSCLC after erlotinib treatment failure compared with results from pre-treatment samples ( 49 ).…”

Section: Nf-kb Pathwaymentioning

confidence: 99%

Preclinical Models for Acquired Resistance to Third-Generation EGFR Inhibitors in NSCLC: Functional Studies and Drug Combinations Used to Overcome Resistance

et al. 2022

View full text Add to dashboard Cite

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are currently recommended as first-line treatment for advanced non-small-cell lung cancer (NSCLC) with EGFR-activating mutations. Third-generation (3rd G) EGFR-TKIs, including osimertinib, offer an effective treatment option for patients with NSCLC resistant 1st and 2nd EGFR-TKIs. However, the efficacy of 3rd G EGFR-TKIs is limited by acquired resistance that has become a growing clinical challenge. Several clinical and preclinical studies are being carried out to better understand the mechanisms of resistance to 3rd G EGFR-TKIs and have revealed various genetic aberrations associated with molecular heterogeneity of cancer cells. Studies focusing on epigenetic events are limited despite several indications of their involvement in the development of resistance. Preclinical models, established in most cases in a similar manner, have shown different prevalence of resistance mechanisms from clinical samples. Clinically identified mechanisms include EGFR mutations that were not identified in preclinical models. Thus, NRAS genetic alterations were not observed in patients but have been described in cell lines resistant to 3rd G EGFR-TKI. Mainly, resistance to 3rd G EGFR-TKI in preclinical models is related to the activation of alternative signaling pathways through tyrosine kinase receptor (TKR) activation or to histological and phenotypic transformations. Yet, preclinical models have provided some insight into the complex network between dominant drivers and associated events that lead to the emergence of resistance and consequently have identified new therapeutic targets. This review provides an overview of preclinical studies developed to investigate the mechanisms of acquired resistance to 3rd G EGFR-TKIs, including osimertinib and rociletinib, across all lines of therapy. In fact, some of the models described were first generated to be resistant to first- and second-generation EGFR-TKIs and often carried the T790M mutation, while others had never been exposed to TKIs. The review further describes the therapeutic opportunities to overcome resistance, based on preclinical studies.

show abstract

Targeting Aurora B kinase prevents and overcomes resistance to EGFR inhibitors in lung cancer by enhancing BIM- and PUMA-mediated apoptosis

Cited by 89 publications

References 64 publications

A Transcriptome Sequencing Study on Genome-Wide Gene Expression Differences of Lung Cancer Cells Modulated by Fucoidan

A Transcriptome Sequencing Study on Genome-Wide Gene Expression Differences of Lung Cancer Cells Modulated by Fucoidan

Sequence-dependent synergistic effect of aumolertinib-pemetrexed combined therapy on EGFR-mutant non-small-cell lung carcinoma with pre-clinical and clinical evidence

Preclinical Models for Acquired Resistance to Third-Generation EGFR Inhibitors in NSCLC: Functional Studies and Drug Combinations Used to Overcome Resistance

Contact Info

Product

Resources

About