scholarly journals SHP2 inhibition enhances the anticancer effect of Osimertinib in EGFR T790M mutant lung adenocarcinoma by blocking CXCL8 loop mediated stemness

2021 ◽  
Author(s):  
Leiming Xia ◽  
Fan Yang ◽  
Suzhi Li ◽  
Chen Kan ◽  
Hong Zheng ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Drug Resistance ◽  
Lung Adenocarcinoma ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Cxcl8 Secretion ◽  
The Impact ◽  
Egfr Tki ◽  
Egfr T790m

Abstract Background: Additional epidermal growth factor receptor (EGFR) mutations confer the drug resistance to generations of EGFR targeted tyrosine kinase inhibitor (EGFR-TKI), which is the thorny challenge to propel the treatment of lung adenocarcinoma (LUAD) forward. In the tailored targeting era, the strategy of EGFR-TKI combined regimen was considered the promising approach to conquer the big aforesaid question. The mechanism of SHP2 involved in the cell proliferation, cytokine production, stemness maintenance and drug resistance of LUAD was not yet fully explored.Methods: To determine the impact of SHP2 on the efficacy of EGFR T790M mutant LUAD cells to Osimertinib, SHP2 was tested in Osimertinib treated LUAD cells. Cell proliferation and stemness were tested in SHP2 modified LUAD cells. RNA sequencing were performed to explore the mechanism of SHP2 promoted stemness.Results: This study demonstrated that high SHP2 indicates poor outcome of LUAD patients, and enriched in Osimertinib resistant LUAD cells. Moreover, SHP2 inhibition suppressed the cell proliferation and damaged the stemness of EGFR T790M mutant LUAD. Furthermore, SHP2 facilitates the CXCL8 secretion of EGFR T790M mutant LUAD which derived from a CXCL8-CXCR1/2 positive feedback loop that promoted the stemness and tumorigenesis. Finally, we found SHP2 inhibited ERK-AKT-NFκB and GSK3β-β Catenin pathways in EGFR T790M mutant LUAD cells, inactivation of NF-κB confers to a blockage of CXCL8-CXCR1/2 loop, and stemness limited by restricting GSK3β/β-Catenin signaling.Conclusions: Our data revealed that inhibition of SHP2 enhances the anti-cancer effect of Osimertinib in EGFR T790M mutant LUAD by blocking CXCL8-CXCR1/2 loop mediated stemness, which may provide an alternative option to promote the efficacy of osimertinib in clinic of EGFR T790M mutant LUAD.

scholarly journals SHP2 inhibition enhances the anticancer effect of Osimertinib in EGFR T790M mutant lung adenocarcinoma by blocking CXCL8 loop mediated stemness

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Leiming Xia ◽  
Fan Yang ◽  
Xiao Wu ◽  
Suzhi Li ◽  
Chen Kan ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Drug Resistance ◽  
Lung Adenocarcinoma ◽  
Feedback Loop ◽  
Kinase Inhibitor ◽  
Therapeutic Option ◽  
Egfr Mutations ◽  
The Impact ◽  
Egfr Tki ◽  
Egfr T790m

Abstract Background Additional epidermal growth factor receptor (EGFR) mutations confer the drug resistance to generations of EGFR targeted tyrosine kinase inhibitor (EGFR-TKI), posing a major challenge to developing effective treatment of lung adenocarcinoma (LUAD). The strategy of combining EGFR-TKI with other synergistic or sensitizing therapeutic agents are considered a promising approach in the era of precision medicine. Moreover, the role and mechanism of SHP2, which is involved in cell proliferation, cytokine production, stemness maintenance and drug resistance, has not been carefully explored in lung adenocarcinoma (LUAD). Methods To evaluate the impact of SHP2 on the efficacy of EGFR T790M mutant LUAD cells to Osimertinib, SHP2 inhibition was tested in Osimertinib treated LUAD cells. Cell proliferation and stemness were tested in SHP2 modified LUAD cells. RNA sequencing was performed to explore the mechanism of SHP2 promoted stemness. Results This study demonstrated that high SHP2 expression level correlates with poor outcome of LUAD patients, and SHP2 expression is enriched in Osimertinib resistant LUAD cells. SHP2 inhibition suppressed the cell proliferation and damaged the stemness of EGFR T790M mutant LUAD. SHP2 facilitates the secretion of CXCL8 cytokine from the EGFR T790M mutant LUAD cells, through a CXCL8-CXCR1/2 positive feedback loop that promotes stemness and tumorigenesis. Our results further show that SHP2 mediates CXCL8-CXCR1/2 feedback loop through ERK-AKT-NFκB and GSK3β-β-Catenin signaling in EGFR T790M mutant LUAD cells. Conclusions Our data revealed that SHP2 inhibition enhances the anti-cancer effect of Osimertinib in EGFR T790M mutant LUAD by blocking CXCL8-CXCR1/2 loop mediated stemness, which may help provide an alternative therapeutic option to enhance the clinical efficacy of osimertinib in EGFR T790M mutant LUAD patients.

Detection of EGFR mutations in NSCLC patients in clinical practice: Comparison between cobas and Scorpion ARMS method.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23101-e23101
Author(s):  
Natsuki Takano ◽  
Satoru Kitazono ◽  
Ryo Ariyasu ◽  
Junji Koyama ◽  
Masafumi Saiki ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Detection Rate ◽  
Egfr Mutation ◽  
Kinase Inhibitor ◽  
De Novo ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Detection Rates ◽  
Initial Biopsy ◽  
Egfr Tki

e23101 Background: Epidermal growth factor receptor (EGFR) mutation is the most important factor for determining the treatment strategy for non-small-cell lung cancers (NSCLCs). Currently, two methods (cobas and Scorpion ARMS) have been approved as companion diagnostics for using EGFR tyrosine kinase inhibitor (TKI). Although there are some differences in the spectrums and sensitivities for detecting EGFRmutations such as exon 19 deletions (ex19del), L858R and T790M mutations, the extent of the differences affecting clinical practice is unclear. Methods: All patients with NSCLC who underwent EGFR mutation tests and treated at our hospital from February 2014 to February 2016 were enrolled. To detect EGFR mutations, the Scorpion ARMS (S) method was used from 2014 to 2015 and thecobasEGFR Mutation Test (C) from 2015 to 2016. We retrospectively investigated the detection rate of each EGFRmutation type and compared the rates between the two methods. Results: A total of 1,287 patients were enrolled. To detect EGFR mutations, 627 patients were tested by the S method and 660 by the C method, respectively. Of 1287 patients, 910 patients underwent initial biopsy, whereas 121 patients underwent re-biopsy after EGFR-TKI failure. EGFRmutations were detected in 130 of 418 (31.1%) patients and 153 of 492 (31.1%) patients by the S and C methods, respectively in the initial biopsy (P = 0.982). However, the detection rate of ex19del was slightly lower in the S method (12.6%) than in the C method (16.3%) (P = 0.105). Conversely, the detection rate of L858R was lower in the C method (13.8%) than in the S method (16.7%), but the difference was not significant (P = 0.252). De novo T790M was detected in one (0.2%) patient by the S method and in none by the C method. In re-biopsy after EGFR-TKI failure, the detection rates of T790M were as follows: 19 of 55 patients (34.5%) by the S method and 20 of 66 (30.3%) by the C method (P = 0.619). Conclusions: The different spectrums and sensitivities of EGFR mutations between the S and C methods were observed; however, they did not significantly affect clinical practice.

Management of medical inoperable and tyrosine kinase inhibitor-naive early-stage lung adenocarcinoma with epidermal growth factor receptor mutations: A retrospective multi-institutional analysis.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21082-e21082
Author(s):  
Yue Mei Sun ◽  
Ming Xiu Zhou ◽  
Ming Zeng
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Lung Adenocarcinoma ◽  
Kinase Inhibitor ◽  
Early Stage ◽  
Growth Factor Receptor ◽  
Epidermal Growth ◽  
Egfr Mutant ◽  
Egfr Tki

e21082 Background: The clinical value of combined local radiation and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) and for medical inoperable and TKI-naïve early-stage lung adenocarcinoma patients with EGFR mutations is not yet determined. In this study, we aimed to pool multi-institutional data to compare the therapeutic effect of EGFR-TKI alone and combined radiation and TKI on the survival outcomes in this patient subgroup. Methods: 132 cases of medical non-operable stage I to III EGFR mutant lung adenocarcinoma were retrospectively reviewed based on data from 5 centers. Among the patients, 65 cases received combined radiation and EGFR-TKI therapy (R+TKI) (49.2%), while 67 cases had EGFR-TKI (50.8%) treatment alone. All patients were followed until death. Results: For R+TKI group, the median overall survival (OS) after primary therapy was 42.6 months, while that of the TKI alone group was 29.4 months (log-rank p < .001). In terms of progression-free survival (PFS), the median PFS in these two treatment groups were 24 months and 14.7 months respectively (log-rank p < .001). Multivariate analysis showed that R+TKI was independently associated with improved OS (adjusted HR: 0.420; 95% CI, 0.287 to 0.614; p < .001) and PFS (adjusted HR: 0.420; 95% CI, 0.291 to 0.605; p < .001) compared to TKI alone. Subgroup analysis confirmed the significant OS benefits in stage III patients and RFS benefits in stage II/III patients. Conclusions: Upfront radiation to primary sites with TKI to follow was a feasible option for patients with EGFR-mutant medical inoperable non-small-cell lung carcinoma (NSCLC) during first-line EGFR-TKI treatment, with significantly improved PFS and OS compared with TKI alone

scholarly journals Lung adenocarcinoma in a patient with Li–Fraumeni syndrome bearing a novel germ-line mutation, TP53R333Vfs*12

2020 ◽  
Vol 50 (10) ◽  
pp. 1214-1217 ◽  
Author(s):  
Shodai Takahashi ◽  
Kazuhiro Shimazu ◽  
Koya Kodama ◽  
Koji Fukuda ◽  
Taichi Yoshida ◽  
...  
Keyword(s):  
Bone Metastasis ◽  
Lung Adenocarcinoma ◽  
Egfr Mutation ◽  
Kinase Inhibitor ◽  
Germ Line ◽  
Growth Factor Receptor ◽  
Triple Mutant ◽  
Li Fraumeni Syndrome ◽  
Li Fraumeni ◽  
Egfr Tki

Abstract Germline mutations of TP53 are responsible for Li–Fraumeni syndrome in its 60–80%. We found a novel germline mutation, TP53: c.997del:p.R333Vfs*12 (NM_000546.6, GRCh, 17:7670713..7670713). The proband is a 40-year-old female, who was suffered from osteosarcoma in her right forearm at her age of 11. She was also suffered from lung adenocarcinoma in her right upper lobe and bone metastasis in her right scapula at her age of 37. She was treated with gefitinib, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) because of EGFR mutation (L747-S752 del). Her bone metastasis became resistant after 1-year treatment. Bone metastasis had an additional EGFR mutation (T790M). The secondary treatment with osimertinib, an another EGFR-TKI, can successfully control the tumors for over 2 years. This TP53 mutation (R333Vfs*12) was first found in lung adenocarcinomas. The therapeutic effect of osimertinib for this triple mutant lung adenocarcinoma is better than the previous report.

scholarly journals Progress toward resistance mechanism to epidermal growth factor receptor tyrosine kinase inhibitor

2016 ◽  
Vol 11 (1) ◽  
pp. 427-431
Author(s):  
Lingling Zhang ◽  
Xiaoxue Zhang ◽  
Liang Zhao
Keyword(s):  
Drug Resistance ◽  
Epidermal Growth Factor Receptor ◽  
Signaling Pathway ◽  
Receptor Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Egfr Signaling ◽  
Egfr Signaling Pathway ◽  
Epidermal Growth ◽  
Egfr Tki

AbstractThe EGFR signaling pathway plays an important role in the occurrence and development of many malignant tumors. It has become a hot spot in the treatment of advanced cancer. At present, the small molecule epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has been shown to advanced non-small-cell lung cancer (NSCLC), has a marked drug resistance or has developed one. The EGFR signaling pathway regulates a variety of cellular functions, and its drug resistance may be related to a number of signal transduction pathways, including drug resistance mutations, structural activation, downstream signaling pathway activation and VEGF expression changes, and so on. In this paper, we review the production mechanism of EGFR-TKI drug resistance.

Treating Patients With EGFR-Sensitizing Mutations: First Line or Second Line—Is There a Difference?

2013 ◽  
Vol 31 (8) ◽  
pp. 1081-1088 ◽  
Author(s):  
Tony Mok ◽  
Jin-Ji Yang ◽  
Kwok-Chi Lam
Keyword(s):  
Drug Exposure ◽  
Tumor Response ◽  
Kinase Inhibitor ◽  
Performance Status ◽  
Egfr Mutations ◽  
Poor Performance Status ◽  
Second Line ◽  
First Line ◽  
The Impact ◽  
Egfr Tki

First-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) is a standard treatment for patients with activating EGFR mutations. Six randomized studies have demonstrated consistent improvement in tumor response rate and progression-free survival over platinum-based combination chemotherapy. The only reason to consider EGFR TKI as second-line therapy is that none of the six comparative studies has shown improvement in overall survival, which can be explained by the high proportion of patients from the chemotherapy arm crossing over to the EGFR TKI arm on progression. It is true that patients with EGFR mutations may benefit from second-line EGFR TKI therapy, but we cannot conclude that the benefit is either equal to or inferior to first-line EGFR TKI therapy. To date, there are no direct comparative data between first- and second-line EGFR TKI in patients with activating EGFR mutations. Tumor response rates to second-line EGFR TKI have been inconsistent, which could potentially be explained by the impact of first-line chemotherapy on the abundance of tumor cells with activating EGFR mutations. However, numerous arguments, including assurance on drug exposure, improvement in quality of life, better tolerance by patients with poor performance status, and deferral of whole-brain radiation therapy for patients with brain metastasis, support the general application of first-line EGFR TKI.

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