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Targeting apoptosis to manage acquired resistance to third generation EGFR inhibitors

《医学前沿(英文)》 2022年 第16卷 第5期   页码 701-713 doi: 10.1007/s11684-022-0951-0

摘要: A significant clinical challenge in lung cancer treatment is management of the inevitable acquired resistance to third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs), such as osimertinib, which have shown remarkable success in the treatment of advanced NSCLC with EGFR activating mutations, in order to achieve maximal response duration or treatment remission. Apoptosis is a major type of programmed cell death tightly associated with cancer development and treatment. Evasion of apoptosis is considered a key hallmark of cancer and acquisition of apoptosis resistance is accordingly a key mechanism of drug acquired resistance in cancer therapy. It has been clearly shown that effective induction of apoptosis is a key mechanism for third generation EGFR-TKIs, particularly osimertinib, to exert their therapeutic efficacies and the development of resistance to apoptosis is tightly associated with the emergence of acquired resistance. Hence, restoration of cell sensitivity to undergo apoptosis using various means promises an effective strategy for the management of acquired resistance to third generation EGFR-TKIs.

关键词: acquired resistance     EGFR inhibitor     apoptosis     lung cancer    

Mechanisms of resistance to third-generation EGFR tyrosine kinase inhibitors

null

《医学前沿(英文)》 2016年 第10卷 第4期   页码 383-388 doi: 10.1007/s11684-016-0488-1

摘要:

The tyrosine kinase inhibitors (TKI) of the epidermal growth factor receptor (EGFR) are becoming the first line of therapy for advanced non-small cell lung cancer (NSCLC). Acquired mutations in EGFR account for one of the major mechanisms of resistance to the TKIs. Three generations of EGFR TKIs have been used in clinical applications. AZD9291 (osimertinib; Tagrisso) is the first and only FDA approved third-generation EGFR TKI for T790M-positive advanced NSCLC patients. However, resistance to AZD9291 arises after 9–13 months of therapy. The mechanisms of resistance to third-generation inhibitors reported to date include the EGFR C797S mutation, EGFR L718Q mutation, and amplifications of HER-2, MET, or ERBB2. To overcome the acquired resistance to AZD9291, EAI045 was discovered and recently reported to be an allosteric EGFR inhibitor that overcomes T790M- and C797S-mediated resistance. This review summarizes recent investigations on the mechanisms of resistance to the EGFR TKIs, as well as the latest development of EAI045 as a fourth-generation EGFR inhibitor.

关键词: EGFR     tyrosine kinase inhibitor     AZD9291     EAI045    

Growth suppression of colorectal cancer expressing S492R EGFR by monoclonal antibody CH12

Qiongna Dong, Bizhi Shi, Min Zhou, Huiping Gao, Xiaoying Luo, Zonghai Li, Hua Jiang

《医学前沿(英文)》 2019年 第13卷 第1期   页码 83-93 doi: 10.1007/s11684-019-0682-z

摘要:

Colorectal cancer (CRC) is a common malignant tumor in the digestive tract, and 30%–85% of CRCs express epidermal growth factor receptors (EGFRs). Recently, treatments using cetuximab, also named C225, an anti-EGFR monoclonal antibody, for CRC have been demonstrated to cause an S492R mutation in EGFR. However, little is known about the biological function of S492R EGFR. Therefore, we attempted to elucidate its biological function in CRC cells and explore new treatment strategies for this mutant form. Our study indicated that EGFR and S492R EGFR accelerate the growth of CRC cells in vitro and in vivo and monoclonal antibody CH12, which specifically recognizes an EGFR tumor-specific epitope, can bind efficiently to S492R EGFR. Furthermore, mAb CH12 showed significantly stronger growth suppression activities and induced a more potent antibody-dependent cellular cytotoxicity effect on CRC cells bearing S492R EGFR than mAb C225. mAb CH12 obviously suppressed the growth of CRC xenografts with S492R EGFR mutations in vivo. Thus, mAb CH12 may be a promising therapeutic agent in treating patients with CRC bearing an S492R EGFR mutation.

关键词: S492R EGFR ectodomain mutation     colorectal cancer     mAb CH12     immunnotherapy    

Ultraviolet-B induced expression of hypoxia-inducible factor 1α, transferrin receptor through EGFR/PI3K

LI Yanhua, BI Zhigang

《医学前沿(英文)》 2007年 第1卷 第1期   页码 79-86 doi: 10.1007/s11684-007-0016-4

摘要: The aim of this research was to explore the effects and signaling pathway of ultraviolet-B (UVB) irradiation on the expression of hypoxia-inducible factor 1α (HIF-1α) and transferrin receptor (TfR). HIF-1α protein was measured by Western blot method. Expressions of epidermal growth factor receptor (EGFR), phosphor-EGF-R and TfR after UVB irradiation were determined with flow cytometry. After UVB irradiation, mRNA levels of HIF-1α and TfR were detected by real time-PCR. Results showed that compared with control groups, UVB was able to induce HIF1α and TfR protein expression in a dose- and time-dependent manner in HaCat cells (<0.05). TfR mRNA was expressed in a dose-dependent manner and reached a peak at the 8th hour in HaCat cells (<0.05) whereas HIF-1α mRNA expression was not affected by UVB treatment (>0.05). The EGFR/PI3K/AKT signaling pathway was required for the induction of HIF-1α and TfR expression induced by UVB. UVB induced activation of EGFR in HaCat cells and EGFR regulated expression of TfR and HIF-1α. EGFR (-/-) MEF did not increase the HIF1 expression following UVB irradiation (>0.05). In contrast, EGFR (+/+) MEF strongly enhanced HIF1α expression after UVB irradiation (<0.05). PD153035, a selective inhibitor of EGFR tyrosine kinase, inhibited the TfR protein expression in UVB-treated cells in a dose-dependent manner (P<0.05). PI3K inhibitors, LY294002 and wortmannin, inhibited HIF-1? and TfR expressions induced by UVB (P<0.05). The DEC1 (-/-) Ha-Cat cells did not increase their TfR and HIF-1α expressions following UVB irradiation (>0.05). In contrast, DEC1 (+/+) HaCat cells strongly enhanced TfR and HIF-1? protein expression after UVB irradiation (P<0.05). We conclude that UVB induces TfR and HIF-1αexpressions via EGFR/PI3K/AKT/DEC1 signaling pathway.

CD47 blockade improves the therapeutic effect of osimertinib in non-small cell lung cancer

《医学前沿(英文)》 2023年 第17卷 第1期   页码 105-118 doi: 10.1007/s11684-022-0934-1

摘要: The third-generation epidermal growth factor receptor (EGFR) inhibitor osimertinib (OSI) has been approved as the first-line treatment for EGFR-mutant non-small cell lung cancer (NSCLC). This study aims to explore a rational combination strategy for enhancing the OSI efficacy. In this study, OSI induced higher CD47 expression, an important anti-phagocytic immune checkpoint, via the NF-κB pathway in EGFR-mutant NSCLC HCC827 and NCI-H1975 cells. The combination treatment of OSI and the anti-CD47 antibody exhibited dramatically increasing phagocytosis in HCC827 and NCI-H1975 cells, which highly relied on the antibody-dependent cellular phagocytosis effect. Consistently, the enhanced phagocytosis index from combination treatment was reversed in CD47 knockout HCC827 cells. Meanwhile, combining the anti-CD47 antibody significantly augmented the anticancer effect of OSI in HCC827 xenograft mice model. Notably, OSI induced the surface exposure of “eat me” signal calreticulin and reduced the expression of immune-inhibitory receptor PD-L1 in cancer cells, which might contribute to the increased phagocytosis on cancer cells pretreated with OSI. In summary, these findings suggest the multidimensional regulation by OSI and encourage the further exploration of combining anti-CD47 antibody with OSI as a new strategy to enhance the anticancer efficacy in EGFR-mutant NSCLC with CD47 activation induced by OSI.

关键词: osimertinib     anti-CD47 antibody     combination strategy     ADCP     EGFR    

标题 作者 时间 类型 操作

Targeting apoptosis to manage acquired resistance to third generation EGFR inhibitors

期刊论文

Mechanisms of resistance to third-generation EGFR tyrosine kinase inhibitors

null

期刊论文

Growth suppression of colorectal cancer expressing S492R EGFR by monoclonal antibody CH12

Qiongna Dong, Bizhi Shi, Min Zhou, Huiping Gao, Xiaoying Luo, Zonghai Li, Hua Jiang

期刊论文

Ultraviolet-B induced expression of hypoxia-inducible factor 1α, transferrin receptor through EGFR/PI3K

LI Yanhua, BI Zhigang

期刊论文

CD47 blockade improves the therapeutic effect of osimertinib in non-small cell lung cancer

期刊论文