Degradation of MCL-1 by bufalin reverses acquired resistance to osimertinib in EGFR-mutant lung cancer

Cao, Fei; Gong, Y.H.; Kang, Xiaohong; Lu, Zhihong; Wang, Ying; Zhao, Kelei; Miao, Zhanhui; Liao, Min; Xu, Zhen-ye

doi:10.1016/j.taap.2019.114662

Cited by 32 publications

(14 citation statements)

References 44 publications

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“…Recently, accumulating evidence indicate that destruction of Mcl-1 enhanced TKI sensitivity. Degradation of Mcl-1 by bufalin reverses acquired resistance to osimertinib in EGFR-mutant lung cancer 58 , and modulation of MEK/ERK-dependent Bim and Mcl-1 degradation overcoming acquired resistance to osimertinib 59 . Additionally, depletion of FBW7 results in upregulation of Mcl-1 protein level and confers TKI resistance in PC9 cells 60 , indicating that reduction of Mcl-1 protein level as a strategy to overcome TKI resistance in NSCLC treatment.…”

Section: Discussionmentioning

confidence: 99%

Deguelin suppresses non-small cell lung cancer by inhibiting EGFR signaling and promoting GSK3β/FBW7-mediated Mcl-1 destabilization

Gao

et al. 2020

Cell Death Dis

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Activating mutations of epidermal growth factor receptor (EGFR) play crucial roles in the oncogenesis of human nonsmall cell lung cancer (NSCLC). By screening 79 commercially available natural products, we found that the natural compound deguelin exhibited a profound anti-tumor effect on NSCLC via directly down-regulating of EGFR-signaling pathway. Deguelin potently inhibited in vitro EGFR kinase activity of wild type (WT), exon 19 deletion, and L858R/ T790M-mutated EGFR. The in silico docking study indicated that deguelin was docked into the ATP-binding pocket of EGFRs. By suppression of EGFR signaling, deguelin inhibited anchorage-dependent, and independent growth of NSCLC cell lines, and significantly delayed tumorigenesis in vivo. Further study showed that deguelin inhibited EGFR and downstream kinase Akt, which resulted in the activation of GSK3β and eventually enhanced Mcl-1 phosphorylation at S159. Moreover, deguelin promoted the interaction between Mcl-1 and E3 ligase SCF FBW7 , which enhanced FBW7-mediated Mcl-1 ubiquitination and degradation. Additionally, phosphorylation of Mcl-1 by GSK3β is a prerequisite for FBW7-mediated Mcl-1 destruction. Depletion or pharmacological inactivation of GSK3β compromised deguelin-induced Mcl-1 ubiquitination and reduction. Taken together, our data indicate that enhancement of ubiquitination-dependent Mcl-1 turnover might be a promising approach for cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Deguelin suppresses non-small cell lung cancer by inhibiting EGFR signaling and promoting GSK3β/FBW7-mediated Mcl-1 destabilization

Gao

et al. 2020

Cell Death Dis

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“…Since Bim‐KO in PC‐9/GR/AP cells also protected the cells from undergoing apoptosis induced by the combination of HNK and Osim, it is fair to conclude that enhanced Bim elevation may also contribute to augmented induction of apoptosis by HNK and Osim combination at least in some Osim‐resistant cell lines (e.g., PC‐9/GR/AR). A recent study has shown that the natural product, bufalin, can reverse acquired resistance to Osim through induction of Ku70‐mediated Mcl‐1 degradation (Cao et al , ). Moreover, it has been shown that EGFR‐mutant NSCLC cells tolerated to short‐term EGFR‐TKI treatment possess elevated Mcl‐1 levels and can be sensitized to EGFR‐TKIs by targeting Mcl‐1 (Song et al , ).…”

Section: Discussionmentioning

confidence: 99%

Overcoming acquired resistance of EGFR‐mutant NSCLC cells to the third generation EGFR inhibitor, osimertinib, with the natural product honokiol

et al. 2020

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The development of acquired resistance to osimertinib (Osim) (AZD9291 or TAGRISSOTM), an FDA‐approved third‐generation epidermal growth factor receptor (EGFR) inhibitor for the treatment of EGFR‐mutant nonsmall cell lung cancer (NSCLC), limits the long‐term benefits for patients. Thus, effective treatment options are urgently needed. To this end, we explored whether honokiol (HNK), a natural product with potential antitumor activity, may be used to overcome Osim resistance. The combination of HNK and Osim synergistically decreased the survival of several Osim ‐resistant cell lines with enhanced effects on inhibiting cell colony formation and growth and on inducing apoptosis. This combination also showed greater growth suppression of Osim‐resistant xenograft tumors including those with 19del, T790M, and C797S triple mutations in nude mice. Mechanistically, the augmented induction of apoptosis by the combination is largely due to enhanced Mcl‐1 reduction through facilitating its degradation. A synthetic HNK derivative exerted similar effects with greater efficacy. Our findings warrant further study of HNK and its derivatives in overcoming Osim resistance in the clinic.

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“…上述研究表明, 参芪扶正注射液初步显示了其逆转肿瘤耐药的潜力, 但具体机制尚不清楚, 未来有待进一步挖掘. 的耐药 [63,64] . 在肝癌中, 蟾毒灵可通过抑制Akt信号通路逆转肝细胞性肝癌对索拉非尼的耐药, 同时具有逆转多药耐药潜能 [65,66] .…”

Section: 研究显示参芪扶正注射液与抗肿瘤药物联用可以起unclassified

Combination of Chinese and western medicine to prevent and reverse resistance of cancer cells to anticancer drugs

Zhang

Huang

et al. 2020

Chin. Sci. Bull.

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Degradation of MCL-1 by bufalin reverses acquired resistance to osimertinib in EGFR-mutant lung cancer

Cited by 32 publications

References 44 publications

Deguelin suppresses non-small cell lung cancer by inhibiting EGFR signaling and promoting GSK3β/FBW7-mediated Mcl-1 destabilization

Deguelin suppresses non-small cell lung cancer by inhibiting EGFR signaling and promoting GSK3β/FBW7-mediated Mcl-1 destabilization

Overcoming acquired resistance of EGFR‐mutant NSCLC cells to the third generation EGFR inhibitor, osimertinib, with the natural product honokiol

Combination of Chinese and western medicine to prevent and reverse resistance of cancer cells to anticancer drugs

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