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Minhua Ye
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P1.16 - Treatment in the Real World - Support, Survivorship, Systems Research (ID 186)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Treatment in the Real World - Support, Survivorship, Systems Research
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.16-24 - Detection of Plasma T790M Mutation After the First Generation EGFR-TKI Resistance of Non-Small Cell Lung Cancer in the Real World (Now Available) (ID 304)
09:45 - 18:00 | Author(s): Minhua Ye
- Abstract
Background
The epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) has shown efficacy in mutation non-small cell lung cancer(NSCLC), but acquired resistance is inevitable. It has been confirmed that the secondary EGFR Thr790Met (T790M) mutation accounted for about 50% at acquired resistance in tumor tissue. The third generation EGFR-TKI had significantly efficacy in T790M positive NSCLC . The purpose of this study was to investigate the positive rate of plasma T790M mutation and its relationship among the clinical characteristics and the frequency of T790M mutation in acquired resistance after first line EGFR‒ TKI treatment in the real world.
Method
Patients were recruited prospective from September 2017 to June 2018.The eligibility criteria of the trial included:1. Older than 18 years, histologically confirmed NSCLC stageⅢB/Ⅳ, EGFR mutation positive; 2.Had progressive disease (PD) after first generation EGFR-TKI by RECIST, PFS>3months; 3.excluded patients who had recevied the third generation TKI treatment. All patients take 10 ml of blood, and detected the T790M gene by amplification refractory mutation system(ARMS). The study was approved by the Ethics Committee of Taizhou Hospital, ethical batch number: 201637.
Result
189 patients are in the analysis (Table 1). The overall plasma T790M mutation rate was 36.51 % (69/189). The positive rate of T790M mutation after the failure of first generation EGFR-TKI treatment was not correlated with the patient's age, sex and the type of first generation TKI drugs. However, it is related to the mutation type of EGFR in baseline and the mode of progression according to Wu YL et al. reports. The frequency of T790M mutation among patients with initial exon 19 deletion mutation, exon 21 L858R point mutation, and other mutations were 45.44%, 26.19% and 33.33%. The mutation rate of T790M in 19del mutant patients was higher than that of L858R mutation and other mutations (p=0.026). The frequency of T790M mutation in local progression patients was 50% after the first generation EGFR TKI was resistant to drug, when in gradual progression was 26.92%, and in dramatic progression was 38.10%. The frequency of T790M mutation of patients with local progression was significantly higher (p=0.031).
ConclusionTable 1 Univariate analysis of the association between patients' characteristics and plasma T790M status.
Characteristics
NO.
Plasma T790M mutation states
P value
Positive (+)
Negative(-)
Age（yr）
≤60
64
25(39.1%)
39(60.9%)
P=0.438
＞60
125
44(35.2%)
81(64.8%)
Sex
Male
64
27(42.19%)
37(57.81%)
P=0.246
Female
125
42(33.6%)
83(66.4%)
Baseline EGFR mutation status
19-del
99
45(45.45%)
54(54.55%)
P=0.026
21-L858R
84
22(26.19%)
62(73.91%)
others
6
2(33.33%)
4(66.67%)
First generation TKI
Lcotinib
96
28(29.17%)
68(70.83%)
P=0.074
Gefitinib
90
39(43.33%)
51(56.67%)
Erlotinib
3
2(66.67%)
1(33.33%)
Disease progression modes
Gradual progression
78
21(26.92%)
57(73.08%)
P=0.031
Local progression
48
24(50%)
24(50%)
Dramatic progression
63
24(38.10%)
39(61.90%)
The overall plasma T790M mutation rate was 36.51% after first generation of EGFR-TKI acquired resistance of NSCLC in the real world. The frequency of T790M mutation with initial mutation of 19 Del was higher than that of L858R mutation, and local progression was higher than gradual progression and dramatic progression.
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P2.03 - Biology (ID 162)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.03-05 - PHLPP1 Expression Through AKT and ERK Dual Signaling Pathways May Slow Down the Resistance to TKI in EGFR-Mutated Lung Adenocarcinoma (ID 298)
10:15 - 18:15 | Author(s): Minhua Ye
- Abstract
Background
The epidermal growth factor receptor (EGFR) kinase inhibitors are effective treatments for lung cancers with EGFR activating mutations, but the magnitude of tumor regression varies and drug resistance is unavoidable. Multiple mechanisms of resistance to EGFR-TKIs have been identified, including the occurrence of secondary mutations in the EGFR gene, MET amplification, acquired BRAF rearrangements and activation of bypass pathways. Central to these mechanisms of resistance is the re-activation of AKT and ERK signaling, which enables escape of tumor cells from EGFR inhibitor treatment. However, the mechanisms of reactivation of PI3K-AKT and ERK/MAPK pathway are unclear.
Pleckstrin homology (PH) domain leucine-rich repeat protein phosphatase (PHLPP) acts as tumor suppressors in various types of human cancer by suppressing cell survival pathways and promoting apoptosis through inhibiting AKT and ERK pathway activation. Here, we hypothesize that PHLPP is a key regulator of EGFR-TKI resistance in lung cancer and a potential treatment target for overcoming resistance to EGFR-TKI treatment.
Method
A transcriptomic of PHLPP1 in non-small lung cancer cell according to gefitinib sensitivity obtained from Gene Expression Omnibus (GEO) database under accession number GSE4342 were analysis. The lentivirus-mediated delivery of shRNA was used to generated stable knockdown of PHLPP1 expression lung cancer cells, and retrovirus-mediated delivery was used to generated stable overexpression of PHLPP1 lung cancer cells. Western blotting, real-time PCR (RT-PCR) and immunofluorescence were used to determined PHLPP expression in vitro. PHLPP1 expression in clinical sample was determined by Immunohistochemical (IHC) staining. MTT assay was conducted to determine the cell proliferation. Xenografts bearing PHLPP overexpression and control were evaluated EGFR-TKI induced tumor regression.
Result
PHLPP1 gene expression was higher in gefitinib-sensitive NSCLC cell lines than gefitinib-resistant NSCLC cell lines from a GEO public database. In vitro, EGFR mutated NSCLC cell line HCC827 continuously exposing to gefitinib exhibited dramatically reduced expression of PHLPP1 and increased phosphorylation AKT and ERK. Knockdown of PHLPP1 decreased cell death induced by the EGFR-TKI in EGFR-mutant lung cancer cells, overexpression of PHLPP1 enhanced gefitinib-induced apoptosis in gefitinib-resistance EGFR-mutant lung cancer cells. In xenograft model, overexpression of PHLPP showed significantly more tumor regression after gefitinib treatment at 1-week time point compared to control group. In patients, PHLPP1 were highly expressed in tumors with EGFR common mutations pre- and post-development of resistance to EGFR TKIs. PHLPP1 expression were down regulated in the post-relapse tumor samples compared to that of pre-treatment, and patients with higher PHLPP1 expression in pre-treatment had significantly longer progression-free survival (PFS).
Conclusion
PHLPP loss may be a key molecule contributing to the resistance of EGFR-TKI by activating PI3K-AKT and ERK/MAPK signaling pathway. PHLPP may serve as a potential predictor of EGFR-TKI treatment response in these patients. Up-regulating PHLPP expression may prevent or /and delay the emergence of EGFR-TKI resistance. Further study is warranted to prove PHLPP as an effective strategy.
