BIX01294 inhibits EGFR signaling in EGFR-mutant lung adenocarcinoma cells through a BCKDHA-mediated reduction in the EGFR level

Kim, Ji Hye; Kim, Jong-Wook; Im, Se Seul; Lee, Ji Hyeon; Hwang, Sein; Chang, Eun‐Ju; Shin, Dong Myung; Rho, Jin Kyung; Son, Jaekyoung

doi:10.1038/s12276-021-00715-7

Cited by 7 publications

(3 citation statements)

References 41 publications

(56 reference statements)

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“…Continuous activation of downstream signaling pathways ultimately lead to the development of a variety of tumors. 21,22 In NSCLC, EGFR mutations mainly occur in adenocarcinoma, female, and non-smoking patients, with a positive mutation rate of more than 50%. 23 The most common mutation subtypes were exon 19 deletion mutation and exon 21 L858 R point mutation, which accounted for 91.8% of all mutation types and were EGFR-sensitive mutations.…”

Section: Discussionmentioning

confidence: 99%

Observation on the clinical efficacy and side effects of EGFR-TKI ± chemotherapy in the treatment of EGFR mutation-positive advanced lung adenocarcinoma

Zheng

Cui

2022

Eur J Inflamm

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Objective To assess the clinical efficacy and side effects of EGFR-TKI with or without chemotherapy in the treatment of EGFR mutation-positive advanced lung adenocarcinoma. Methods A total of 103 IIIB or IV EGFR mutation-positive lung adenocarcinoma patients admitted to the oncology department of Fujian Provincial Hospital from January 2017 to October 2020 were selected. According to genetic mutation status, patients were divided into the following groups: 19del alone, 19del combined with TP53 or other co-mutations, L858R mutation alone, and L858R mutation combined with TP53 or other co-mutations. Targeted drugs or targeted drugs combined with chemotherapy were respectively administered in the four groups. In patients with simple 19 deletion, only targeted drugs with no combined therapy were applied, resulting in seven total groups. The difference between short-term treatment and long-term treatment effects and the occurrence of adverse reactions was calculated and compared. Results There was no statistical significance of difference in the incidence of adverse reactions in seven groups ( p > 0.05). The short-term disease control rate of the combination group was higher than the targeted drug group with the difference yielding statistical significance ( p < 0.001). The short-term objective response rate of the combination group was higher than the targeted drug group, also yielding statistical significance ( p < 0.001). By October 2020, the median progression-free survival (PFS) was 16 months in the EGFR-TKI-targeted combined with chemotherapy group and 10 months in the single-drug EGFR-TKI group, and the PFS time was longer in the combination group than in the single targeted drug group, the difference being statistically significant ( p = 0.001). Conclusions In the treatment of advanced lung adenocarcinoma patients with EGFR-gene sensitive mutations, compared with single EGFR-TKI-targeted therapy, EGFR-TKI-targeted drug combined chemotherapy can control the disease progression more effectively, and does not increase adverse reactions.

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Section: Discussionmentioning

confidence: 99%

Observation on the clinical efficacy and side effects of EGFR-TKI ± chemotherapy in the treatment of EGFR mutation-positive advanced lung adenocarcinoma

Zheng

Cui

2022

Eur J Inflamm

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“…As mentioned earlier, the development of G9a inhibitors has been broadly researched. Several G9a inhibitors such as BIX-01294 [ 135 ], UNC0638 [ 136 ], and UNC0642 [ 137 ] blocking the H3 substrate binding site of G9a were designed based on the core of quinazoline. While BIX-01294 and its analogs presented a highly cytotoxicity in cells, UNC0638 showed a poorly pharmacokinetics in vivo [ 138 ].…”

Section: G9a Inhibitorsmentioning

confidence: 99%

Role of HOXA9 in solid tumors: mechanistic insights and therapeutic potential

et al. 2022

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HOXA9 functioning as a transcription factor is one of the members of HOX gene family, which governs multiple cellular activities by facilitating cellular signal transduction. In addition to be a driver in AML which has been widely studied, the role of HOXA9 in solid tumor progression has also received increasing attention in recent years, where the aberrant expression of HOXA9 is closely associated with the prognosis of patient. This review details the signaling pathways, binding partners, post-transcriptional regulation of HOXA9, and possible inhibitors of HOXA9 in solid tumors, which provides a reference basis for further study on the role of HOXA9 in solid tumors.

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“…[ 32 ] Meanwhile, G9A was found to mediate lysine methylation of p53, CCAAT/enhancer bingding protein beta, and forkhead box transcription factor O1 (FOXO1). [ 33 , 34 , 35 ] Mounting evidence suggests the critical regulatory role of KDM3A and G9A in diverse biological events such as metabolism, [ 29 ] cancer progression, [ 36 ] spermatogenesis, [ 37 ] stem cell function, [ 38 ] and sex determination. [ 39 ] In BMSCs, KDM3A and G9A play an essential role in osteogenesis through their classical histone demethylation or methylation activity.…”

Section: Introductionmentioning

confidence: 99%

Lysine 68 Methylation‐Dependent SOX9 Stability Control Modulates Chondrogenic Differentiation in Dental Pulp Stem Cells

et al. 2023

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Dental pulp stem cells (DPSCs), characterized by easy availability, multi‐lineage differentiation ability, and high proliferation ability, are ideal seed cells for cartilage tissue engineering. However, the epigenetic mechanism underlying chondrogenesis in DPSCs remains elusive. Herein, it is demonstrated that KDM3A and G9A, an antagonistic pair of histone‐modifying enzymes, bidirectionally regulate the chondrogenic differentiation of DPSCs by controlling SOX9 (sex‐determining region Y‐type high‐mobility group box protein 9) degradation through lysine methylation. Transcriptomics analysis reveals that KDM3A is significantly upregulated during the chondrogenic differentiation of DPSCs. In vitro and in vivo functional analyses further indicate that KDM3A promotes chondrogenesis in DPSCs by boosting the SOX9 protein level, while G9A hinders the chondrogenic differentiation of DPSCs by reducing the SOX9 protein level. Furthermore, mechanistic studies indicate that KDM3A attenuates the ubiquitination of SOX9 by demethylating lysine (K) 68 residue, which in turn enhances SOX9 stability. Reciprocally, G9A facilitates SOX9 degradation by methylating K68 residue to increase the ubiquitination of SOX9. Meanwhile, BIX‐01294 as a highly specific G9A inhibitor significantly induces the chondrogenic differentiation of DPSCs. These findings provide a theoretical basis to ameliorate the clinical use of DPSCs in cartilage tissue‐engineering therapies.

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BIX01294 inhibits EGFR signaling in EGFR-mutant lung adenocarcinoma cells through a BCKDHA-mediated reduction in the EGFR level

Cited by 7 publications

References 41 publications

Observation on the clinical efficacy and side effects of EGFR-TKI ± chemotherapy in the treatment of EGFR mutation-positive advanced lung adenocarcinoma

Observation on the clinical efficacy and side effects of EGFR-TKI ± chemotherapy in the treatment of EGFR mutation-positive advanced lung adenocarcinoma

Role of HOXA9 in solid tumors: mechanistic insights and therapeutic potential

Lysine 68 Methylation‐Dependent SOX9 Stability Control Modulates Chondrogenic Differentiation in Dental Pulp Stem Cells

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