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Method and application of autophagy inhibitor for overcoming drug resistance in treatment of lung cancer

An autophagy inhibitor and drug resistance technology, which is applied in the field of tumor drug treatment, can solve the problems of drug resistance again, in the preclinical or early stage of clinical trials, and the test results are not very satisfactory, so as to enhance the curative effect and overcome drug resistance Effect

Pending Publication Date: 2019-11-26
THE FIRST AFFILIATED HOSPITAL OF GUANGZHOU MEDICAL UNIV (GUANGZHOU RESPIRATORY CENT)
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  • Abstract
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Problems solved by technology

However, the results of phase I and II clinical trials of newly completed EGFR tyrosine kinase irreversible inhibitors including HKI-272, BIBW2992, XL647 and PF00299804 in the treatment of NSCLC patients with acquired resistance to gefitinib are not very satisfactory. At present, most of these studies are still in the preclinical or early stage of clinical trials; the third-generation EGFR-TKI has also achieved a certain clinical effect, but it still faces the problem of drug resistance again
The above drug resistance mechanisms can only explain about 50% of the drug resistance phenomenon, and the drug resistance mechanism of 50% of patients to EGFR-TKI is still unclear; New strategies for drug resistance appear particularly urgent

Method used

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  • Method and application of autophagy inhibitor for overcoming drug resistance in treatment of lung cancer
  • Method and application of autophagy inhibitor for overcoming drug resistance in treatment of lung cancer
  • Method and application of autophagy inhibitor for overcoming drug resistance in treatment of lung cancer

Examples

Experimental program
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Effect test

Embodiment 1

[0018] Example 1 The role of autophagy in EGFR-TKI drug resistance

[0019] 1. Experimental materials and methods

[0020] RPMI 1640 culture medium and fetal bovine serum were purchased from Gibco, USA; MTT was purchased from Sigma, USA; Erlotinib tablets were purchased from Shanghai Roche Pharmaceutical Co., Ltd.; autophagy-related marker proteins LC3B (#2775), P62 (#5114), Beclin1 ( #3738) and GAPDH (#3683) antibodies were purchased from Cell Signaling Technology; HRP-labeled goat anti-mouse or anti-rabbit IgG were purchased from Cell Signaling Technology.

[0021] 1.2 Induction of PER in PC9 cells and erlotinib-resistant cell lines

[0022] Human lung adenocarcinoma PC9 cells were donated by Professor Zhou Caicun of Shanghai Pulmonary Hospital; the cells were cultured in 1640 medium containing 10% fetal bovine serum at 37 °C and 5% CO2. Erlotinib-resistant cell lines were established by erlotinib dose gradient screening method, starting from 0.02umol / L, gradually increasi...

Embodiment 2

[0030] Example 2 Application of autophagy inhibitors in overcoming EGFR-TKI drug resistance

[0031] 1. Experimental materials and methods

[0032] 1.1 MTT method to detect cell proliferation and inhibition

[0033] PC-9 and PER cells in the logarithmic growth phase were seeded in 96-well plates and cultured in 5% CO2, 37°C, and saturated humidity. When the cells are confluent to 70-80%, discard the original culture medium in the well. Add different concentrations of erlotinib and autophagy inhibitors, or add erlotinib and autophagy inhibitors in combination, add 10 μL MTT to each well after incubation for 48 hours, discard the supernatant after incubation for 4 hours, add 150 μL DMSO to each well, shake for 10 min, the absorbance value was detected by a microplate reader at a wavelength of 450 nm. The cell inhibition rate was calculated by the following formula: cell survival rate% = (average OD value of the experimental group - average OD value of the blank group) / (aver...

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Abstract

The invention relates to the field of tumor drug treatment, in particular to application of an autophagy inhibitor for overcoming drug resistance of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in treatment of non-small cell lung cancer. The autophagy inhibitor is chloroquine. The EGFR-TKI is erlotinib. The method and application has the beneficial effects that autophagy is involved in development of the EGFR-TKI drug resistance of non-small cell lung cancer, the autophagy inhibitor chloroquine can overcome the drug resistance of the EGFR-TKI by inhibiting autophagy, and combination of the chloroquine and the erlotinib can effectively kill lung cancer cells resistant to the erlotinib inside and outside bodies.

Description

technical field [0001] The invention relates to the field of tumor drug treatment, in particular to the application of an autophagy inhibitor used to overcome epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) drug resistance in the treatment of non-small cell lung cancer. Background technique [0002] Lung cancer is one of the most harmful malignant tumors to human health and life in the world today. The morbidity and mortality have shown an obvious upward trend in recent years, seriously threatening human health. Lung cancer is difficult to detect in the early stage, and 70% of lung cancer patients are already in the middle and late stages when they go to the doctor, and the curative effect of conventional radiotherapy and chemotherapy is limited. In recent years, with the continuous elucidation of abnormal signal transduction pathways in lung cancer cells, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (epidermal growth factor recept...

Claims

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Application Information

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IPC IPC(8): A61K31/4706A61K31/517A61P35/00
CPCA61K31/4706A61K31/517A61P35/00
Inventor 周承志刘明汪延生
Owner THE FIRST AFFILIATED HOSPITAL OF GUANGZHOU MEDICAL UNIV (GUANGZHOU RESPIRATORY CENT)
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