Tyrosine Kinase Inhibitors Resistance Research Articles

Identification of six hub genes in mantle cell lymphoma patients with BTKi resistance.

Bruton tyrosine kinase inhibitor (BTKi) resistance is an unsolved problem in the treatment of relapse/recurrence (R/R) mantle cell lymphoma (MCL). Although salvage therapy following ibrutinib resistance has been attempted in recent years, the survival of resistant patients was significantly reduced. Once ibrutinib-treated patients relapse, the 1-year survival rate is only 22%. Acquired drug resistance and primary drug resistance were found to relate closely to genetic mutations. The hub genes identification and clinical data analysis of patients resistant to BTKi based on the Chinese MCL gene mutation profile are worthy of exploration. Based on 28 MCL patients' mutation data and clinical data, 6 hub genes were screened by a gene panel of 69 genes and univariate Cox prognostic analysis. Prognosis and responses to salvage therapy regimen were analyzed. Patients with BTKi had less favorable clinical features at baseline. Chimeric antigen receptor T-cell (CAR-T) therapy yielded the best response among salvage treatments. The 6 hub genes were screened by a gene panel of 69 genes (GP79) which might be a potential predictor for MCL patients with BTKi resistance. The clinical characteristics of BTKi resistance in MCL patients were summarized, and 6 hub genes were identified to provide ideas and suggestions for further research.

33 (PB023) - Establishment and characterization of a preclinical platform of subcutaneous renal cell carcinoma (RCC) patient-derived xenograft models to evaluate novel treatment strategies

Background: Renal cell carcinoma (RCC) is a cancer type with an onset mainly during the sixth or seventh decade of the patient’s life. Patients with advanced or metastasized RCC have a poor prognosis. The majority of patients develop drug resistance towards Standard of Care (SoC) drugs within months. Tyrosine kinase inhibitors (TKI) are used in first-line therapy and have been combined with immune checkpoint inhibitors recently. The development of novel therapies targeting acquired TKI resistance mechanisms in advanced and metastatic RCC remains an urgent medical need.

174 (PB054) - A novel BAD phosphorylation inhibitor combined with EGFR tyrosine kinase inhibitors in EGFR-mutant lung adenocarcinoma treatment

Background: The approval and use of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutant NSCLC has been a breakthrough in clinic. The activation of compensatory pathways of PI3 K/ AKT and/or MEK/MAPK modulates cell survival and drug resistance of lung adenocarcinoma (LUAC). As a convergent downstream signaling node and the determinant, BAD is a potential target to inhibit cell survival and to overcome EGFR TKI resistance in LUAC treatment.

Fasudil Increased the Sensitivity to Gefitinib in NSCLC by Decreasing Intracellular Lipid Accumulation

Simple SummaryThe anti-tumor role of Fasudil in EGFR-mutation NSCLC as well as its mechanism are largely unknown. Here, we show that Fasudil could effectively inhibit EGFR-mutation cell growth and enhance the sensitivity of gefitinib-resistant NSCLC cells to gefitinib by suppressing intracellular lipid accumulation. Mechanistic investigations showed that Fasudil could reverse gefitinib-induced SCD1 expression by suppressing AMPK activity, and combination therapy had a greater inactivation effect on the EGFR/PI3K/AKT pathway than either treatment alone. These findings highlight the clinical significance of Fasudil in EGFR mutation NSCLC therapy.Tyrosine kinase inhibitors (TKIs) resistance is a challenge in patients with epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC). Here, we examined the effect of Fasudil in reversing TKIs resistance. The results of CCK8 assay, clone formation assay, cell cycle arrest analysis, and apoptosis analysis show that Fasudil treatment effectively suppressed the growth and induced apoptosis of the EGFR-mutant NSCLC cells. Furthermore, Fasudil in combination with gefitinib showed a synergistic anti-tumor effect in gefitinib-resistant NSCLC cells. RNA-seq analysis and immunoblotting indicated that Fasudil treatment significantly inhibited intracellular lipid accumulation and EGFR/PI3K/AKT pathway activation. Mechanistic investigations showed that Fasudil regulated lipogenic gene expressions via AMPK signal pathway. In vivo, Fasudil and gefitinib co-administration significantly attenuated the growth of H1975 nude mouse xenograft models, suggesting that Fasudil treatment combined with gefitinib can be applied as a therapy for gefitinib-resistant NSCLC cells.

Study on the mechanism of Astragalus-Panax notoginseng in the treatment of gastric ulcer based on network pharmacology

Objective:To explore the possible mechanism of Astragalus Panax notoginseng in the treatment of GU by using network pharmacology. Methods: combined with the network pharmacology technology, the active components were obtained with the help of tcmsp database, OB≥30% and DL≥0.18 were set, the potential active components were screened, and the drug target information was obtained; After screening the genes, disenem and other important targets in the database; Using venny2 1 software, draw Wayne diagram and obtain drug disease common targets; Using Cytoscape 3.7.2 software, construct the "drug component target disease" network diagram, screen the core genes, and conduct go analysis and KEGG analysis. Results: 27 potential active components, 488 drug targets and 118 drug disease common targets were got. Go enrichment analysis showed that the intersection gene set was enriched to 1948 biological processes, 45 cell component expression processes and 106 processes related to molecular function. KEGG enrichment analysis is mainly based on 146 related signal pathways. The signal pathways of Astragalus Panax notoginseng in the treatment of Gu mainly involve proteoglycans in cancer, prostate cancer, EGFR tyrosine kinase inhibitor resistance and other signal pathways. Conclusion: Astragalus-Panax notoginseng drug pair can treat gastric ulcer through multiple components acting on multiple targets and multiple signal pathways, which preliminarily reveals its mechanism of action and provides a support for further empirical research.

Study on the mechanism of Astragalus-Panax notoginseng in the treatment of gastric ulcer based on network pharmacology

Objective:To explore the possible mechanism of Astragalus Panax notoginseng in the treatment of GU by using network pharmacology. Methods: combined with the network pharmacology technology, the active components were obtained with the help of tcmsp database, OB≥30% and DL≥0.18 were set, the potential active components were screened, and the drug target information was obtained; After screening the genes, disenem and other important targets in the database; Using venny2 1 software, draw Wayne diagram and obtain drug disease common targets; Using Cytoscape 3.7.2 software, construct the "drug component target disease" network diagram, screen the core genes, and conduct go analysis and KEGG analysis. Results: 27 potential active components, 488 drug targets and 118 drug disease common targets were got. Go enrichment analysis showed that the intersection gene set was enriched to 1948 biological processes, 45 cell component expression processes and 106 processes related to molecular function. KEGG enrichment analysis is mainly based on 146 related signal pathways. The signal pathways of Astragalus Panax notoginseng in the treatment of Gu mainly involve proteoglycans in cancer, prostate cancer, EGFR tyrosine kinase inhibitor resistance and other signal pathways. Conclusion: Astragalus-Panax notoginseng drug pair can treat gastric ulcer through multiple components acting on multiple targets and multiple signal pathways, which preliminarily reveals its mechanism of action and provides a support for further empirical research.

HDAC I/IIb selective inhibitor Purinostat Mesylate combined with GLS1 inhibition effectively eliminates CML stem cells.

Purinostat Mesylate (PM) is a novel highly selective and active HDAC I/IIb inhibitor, and the injectable formulation of PM (PMF) based on the compound prescription containing cyclodextrin completely can overcome PM's poor solubility and improves its stability and pharmacokinetic properties. Here, we showed that PM effectively repressed the survival of Ph+ leukemia cells and CD34+ leukemia cells from CML patients in vitro. In vivo studies demonstrated that PMF significantly prevented BCR-ABL(T315I) induced CML progression by restraining leukemia stem cells (LSCs), which are insensitive to chemotherapy and responsible for CML relapse. Mechanism studies revealed that targeting HDAC I/IIb repressed several important factors for LSCs survival including c-Myc, β-Catenin, E2f, Ezh2, Alox5, and mTOR, as well as interrupted some critical biologic processes. Additionally, PMF increased glutamate metabolism in LSCs by increasing GLS1. The combination of PMF and glutaminase inhibitor BPTES synergistically eradicated LSCs by altering multiple key proteins and signaling pathways which are critical for LSC survival and self-renewal. Overall, our findings represent a new therapeutic strategy for eliminating LSCs by targeting HDAC I/IIb and glutaminolysis, which potentially provides a guidance for PMF clinical trials in the future for TKI resistance CML patients.

Mechanisms of resistance to tyrosine kinase inhibitors in liver cancer stem cells and potential therapeutic approaches.

The administration of tyrosine kinase inhibitors (TKIs) for the treatment of advanced-stage patients is common in hepatocellular carcinoma (HCC). However, therapy resistance is often encountered, and its emergence eventually curtails long-term clinical benefits. Cancer stem cells (CSCs) are essential drivers of tumor recurrence and therapy resistance; thus, the elucidation of key hallmarks of resistance mechanisms of liver CSC-driven HCC may help improve patient outcomes and reduce relapse. The present review provides a comprehensive summary of the intrinsic and extrinsic mechanisms of TKI resistance in liver CSCs, which mediate treatment failure, and discusses potential strategies to overcome TKI resistance from a preclinical perspective.

Survey and analysis of the concerns of patients with chronic myeloid leukemia in China in 2021

Objective: To investigate the concerns of adult patients with chronic myeloid leukemia (CML) in the chronic phase receiving tyrosine kinase inhibitor (TKI) therapy in China. Methods: A cross-sectional questionnaire including 23 issues of concern was filled by patients with CML nationwide from August to September 2021. The results were compared with those from 2015 to 2016. Results: Data from 952 questionnaires were analyzed. The five most concerned issues were "TKI-related adverse effects and management" (66%) , "stopping TKI therapy" (46%) , "CML risk assessment" (46%) , "TKI dose reduction" (42%) , and "restrictions in daily life activities" (41%) . Compared with the results from 2015 to 2016, patients paid more attention to "TKI-related adverse effects and management" , "monitoring" , and "interpretation of laboratory reports" (all P<0.01) . Concerns of "TKI reimbursement policies" , "price reduction of TKIs" , and issues related to generic TKIs decreased significantly (all P<0.01) . Multivariate analysis showed that female patients (OR=1.8, 95% CI 1.4-2.5, P<0.001) , elderly patients (OR=1.0, 95% CI 1.0-1.0, P<0.001) , or patients with bachelor's degree or higher (OR=1.8, 95% CI 1.3-2.4, P<0.001) were more concerned with "TKI dose reduction" than others. Patients with a bachelor's degree or higher (OR=1.6, 95% CI 1.2-2.2, P=0.002) paid more attention to "CML risk assessment" , whereas those currently receiving a second- or third-generation TKI therapy (OR=1.9, 95% CI 1.3-2.6, P<0.001) were more concerned about "TKI resistance" . Conclusion: Patients with CML paid the most attention to "TKI-related adverse effects and management" , "stopping TKI therapy" , "CML risk assessment" , "TKI dose reduction" , and "restrictions in daily life activities" . Patients' sociodemographic covariates and treatment status were associated with their concerns.

MET gene amplification is a mechanism of resistance to entrectinib in ROS1+ NSCLC.

ROS1 tyrosine kinase inhibitors (TKIs) have demonstrated significant clinical benefit for ROS1+ NSCLC patients. However, TKI resistance inevitably develops through ROS1 kinase domain (KD) modification or another kinase driving bypass signaling. While multiple TKIs have been designed to target ROS1 KD mutations, less is known about bypass signaling in TKI-resistant ROS1+ lung cancers. Utilizing a primary, patient-derived TPM3-ROS1 cell line (CUTO28), we derived an entrectinib-resistant line (CUTO28-ER). We evaluated proliferation and signaling responses to TKIs, and utilized RNA sequencing, whole exome sequencing, and fluorescence in situ hybridization to detect transcriptional, mutational, and copy number alterations, respectively. We substantiated in vitro findings using a CD74-ROS1 NSCLC patient's tumor samples. Last, we analyzed circulating tumor DNA (ctDNA) from ROS1+ NSCLC patients in the STARTRK-2 entrectinib trial to determine the prevalence of MET amplification. CUTO28-ER cells did not exhibit ROS1 KD mutations. MET TKIs inhibited proliferation and downstream signaling and MET transcription was elevated in CUTO28-ER cells. CUTO28-ER cells displayed extrachromosomal (ecDNA) MET amplification without MET activating mutations, exon 14 skipping, or fusions. The CD74-ROS1 patient samples illustrated MET amplification while receiving ROS1 TKI. Finally, two of 105 (1.9%) entrectinib-resistant ROS1+ NSCLC STARTRK-2 patients with ctDNA analysis at enrollment and disease progression displayed MET amplification. Treatment with ROS1-selective inhibitors may lead to MET-mediated resistance. The discovery of ecDNA MET amplification is noteworthy, as ecDNA is associated with more aggressive cancers. Following progression on ROS1-selective inhibitors, MET gene testing and treatments targeting MET should be explored to overcome MET-driven resistance.

Emerging Role of Noncoding RNAs in EGFR TKI-Resistant Lung Cancer.

Simple SummaryThe introduction of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of lung cancer. Nevertheless, TKI resistance impedes therapeutic efficacy and its underlying mechanisms remain unclear. This review summarizes the potential mechanisms of noncoding RNAs (ncRNAs) in EGFR TKI-resistant lung cancer and their clinical applications. Moreover, we highlight the bottlenecks that urgently need to be addressed to promote the clinical application of ncRNAs.Lung cancer accounts for the majority of malignancy-related mortalities worldwide. The introduction of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) has revolutionized the treatment and significantly improved the overall survival (OS) of lung cancer. Nevertheless, almost all EGFR-mutant patients invariably acquire TKI resistance. Accumulating evidence has indicated that noncoding RNAs (ncRNAs), such as microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), have a central role in the tumorigenesis and progression of lung cancer by regulating crucial signaling pathways, providing a new approach for exploring the underlying mechanisms of EGFR-TKI resistance. Therefore, this review comprehensively describes the dysregulation of ncRNAs in EGFR TKI-resistant lung cancer and its underlying mechanisms. We also underscore the clinical application of ncRNAs as prognostic, predictive and therapeutic biomarkers for EGFR TKI-resistant lung cancer. Furthermore, the barriers that need to be overcome to translate the basic findings of ncRNAs into clinical practice are discussed.

A novel coumarin derivative DBH2 inhibits proliferation and induces apoptosis of chronic myeloid leukemia cells

With the development of tyrosine kinase inhibitor (TKI) resistance, finding the novel effective chemotherapeutic agent is of seminal importance for chronic myelogenous leukemia (CML) treatment. This study aims to find the effective anti-leukemic candidates and investigate the possible underlying mechanism. We synthesized the novel coumarin derivatives and evaluated their anti-leukemic activity. Cell viability assay revealed that compound DBH2 exhibited the potent inhibitory activity on the proliferation of CML K562 cells and TKI resistant K562 cells. Morphological observation and flow cytometry confirmed that DBH2 could selectively induce cell apoptosis and cell cycle arrest at G2/M phase of the K562 cells, which was further confirmed on the bone marrow cells from CML transgenic model mice and CD34+ bone marrow leukemic cells from CML patients. Treatments of DBH2 in combination with imatinib could prolong the survival rate of SCL-tTA-BCR/ABL transgenic model mice significantly. Quantitative RT-PCR revealed that DBH2 inhibited the expression of STAT3 and STAT5 in K562 cells, and caspase-3 knockout alleviated the DBH2 induced apoptosis. Furthermore, DBH2 could induce the expression of PARP1 and ROCK1 in K562 cells, which may play the important role in caspase-dependent apoptosis. Our results concluded that coumarin derivative DBH2 serves as a promising candidate for the CML treatment, especially in the combination with imatinib for the TKI resistant CML, and STAT/caspase-3 pathway was involved in the molecular mechanism of anti-leukemic activity of DBH2.

Chinese herbal formula shen-ling-bai-zhu-san to treat chronic gastritis: Clinical evidence and potential mechanisms.

BACKGROUNDChronic gastritis (CG) is an inflammatory disease of the gastric mucosa. Shen-ling-bai-zhu san (SLBZS), a traditional Chinese medicine formula, is widely used for treating CG. Nevertheless, its effects are currently unclear.AIMTo determine the clinical evidence and potential mechanisms of SLBZS for the treatment of CG.METHODSWe systematically searched 3 English (PubMed, Embase, Medline) and 4 Chinese databases (Cochrane Library Central Register of Controlled Trials, China National Knowledge Infrastructure database, Wanfang Data Knowledge Service Platform, and the VIP information resource integration service platform) without language or publication bias restriction. Qualified studies were selected according to pre-set inclusion and exclusion criteria. RevMan 5.3 software was used for meta-analysis and literature quality assessment, Stata 14.0 software was used for sensitivity analysis, GRADE profiler 3.6 was used to evaluate the quality of evidence. And then, network pharmacology analysis was applied to primary research the mechanisms of action of SLBZS on CG.RESULTSFourteen studies were finally included, covering 1335 participants. Meta-analysis indicated that: (1) SLBZS was superior to conventional therapies [risk ratio (RR): 1.29, 95% confidence interval (CI): 1.21 to 1.37, P < 0.00001]; (2) SLBZS was better than conventional therapies [RR: 0.24, 95% confidence interval (95%CI): 0.11 to 0.55, P = 0.0007] in terms of recurrence rate and reversal of Helicobacter pylori positivity (RR: 1.20, 95%CI: 1.11 to 1.30, P < 0.00001); and (3) The safety of SLBZS for CG remains unclear. According to the GRADE method, the quality of evidence was not high. Besides, SNZJS might treat CG by acting on related targets and pathways such as EGFR tyrosine kinase inhibitor resistance, the PI3K-Akt signaling pathway, and others.CONCLUSIONSLBZS might be useful in treating CG, but long-term effects and specific clinical mechanisms of it maintain unclear. More samples and high-quality clinical experiments should be assessed and verified in the next step.

Protein tyrosine kinase 2b inhibition reverts niche-associated resistance to tyrosine kinase inhibitors in AML

FLT3 tyrosine kinase inhibitor (TKI) therapy evolved into a standard therapy in FLT3-mutated AML. TKI resistance, however, develops frequently with poor outcomes. We analyzed acquired TKI resistance in AML cell lines by multilayered proteome analyses. Leupaxin (LPXN), a regulator of cell migration and adhesion, was induced during early resistance development, alongside the tyrosine kinase PTK2B which phosphorylated LPXN. Resistant cells differed in cell adhesion and migration, indicating altered niche interactions. PTK2B and LPXN were highly expressed in leukemic stem cells in FLT3-ITD patients. PTK2B/FAK inhibition abrogated resistance-associated phenotypes, such as enhanced cell migration. Altered pathways in resistant cells, assessed by nascent proteomics, were largely reverted upon PTK2B/FAK inhibition. PTK2B/FAK inhibitors PF-431396 and defactinib synergized with different TKIs or daunorubicin in FLT3-mutated AML. Midostaurin-resistant and AML cells co-cultured with mesenchymal stroma cells responded particularly well to PTK2B/FAK inhibitor addition. Xenograft mouse models showed significant longer time to leukemia symptom-related endpoint upon gilteritinib/defactinib combination treatment in comparison to treatment with either drug alone. Our data suggest that the leupaxin-PTK2B axis plays an important role in acquired TKI resistance in AML. PTK2B/FAK inhibitors act synergistically with currently used therapeutics and may overcome emerging TKI resistance in FLT3-mutated AML at an early timepoint.

Inhibition of proteasomal deubiquitinases USP14 and UCHL5 overcomes tyrosine kinase inhibitor resistance in chronic myeloid leukaemia.

BackgroundChronic myeloid leukaemia (CML) is a haematological cancer featured by the presence of BCR‐ABL fusion protein with abnormal tyrosine kinase activation. Classical tyrosine kinase inhibitor (TKI)‐based therapies are available to patients with CML. However, acquired resistance to TKI has been a challenging obstacle, especially stubborn T315I mutation is the most common cause. Therefore, it is especially urgent to find more effective targets to overcome TKI resistance induced by BCR‐ABLT315I. Proteasomal deubiquitinases (USP14 and UCHL5) have fundamental roles in the ubiquitin‐proteasome system and possess multiple functions during cancer progression.MethodsThe human peripheral blood mononuclear cells were collected to measure the mRNA expression of USP14 and UCHL5, as well as to detect the toxicity effect of b‐AP15. We explored the effect of b‐AP15 on the activity of proteasomal deubiquitinases. We detected the effects of b‐AP15 on BCR‐ABLWT and BCR‐ABLT315I CML cells in vitro and in the subcutaneous tumour model. We knocked down USP14 and/or UCHL5 by shRNA to explore whether these proteasomal deubiquitinases are required for cell proliferation of CML.ResultsIn this study, we found that increased expression of the proteasomal deubiquitinase USP14 and UCHL5 in primary cancer cells from CML patients compared to healthy donors. b‐AP15, an inhibitor of USP14 and UCHL5, exhibited potent tumour‐killing activity in BCR‐ABLWT and BCR‐ABLT315I CML cell lines, as well as in CML xenografts and primary CML cells. Mechanically, pharmacological or genetic inhibition of USP14 and UCHL5 induced cell apoptosis and decreased the protein level of BCR‐ABL in CML cells expressing BCR‐ABLWT and BCR‐ABLT315I. Moreover, b‐AP15 synergistically enhanced the cytotoxic effect caused by TKI imatinib in BCR‐ABLWT and BCR‐ABLT315I CML cells.ConclusionCollectively, our results demonstrate targeting USP14 and UCHL5 as a potential strategy for combating TKI resistance in CML.

1078P Correlation between T cell immunity and EGFR-TKI treatment in patients harboring EGFR driver mutation

Although osimertinib provides a longer survival time than first/second-generation EGFR tyrosine kinase inhibitor (TKI) for non-small cell lung cancer (NSCLC) harboring EGFR mutations, acquired resistance is inevitable. Since the time to acquire resistance to TKI is shorter for cancers with a higher mutational burden and mutations increase after TKI resistance is acquired, the acquired resistance mechanism depends primarily on acquired mutations. Although the cancer immunoediting theory indicates that the process of genetic mutation accumulation by cancer cells involves a conflict with T-cell immunity, which recognizes gene mutation products as neoantigens and destroys them, the relationship between TKI treatment effect and immunological response in patients with EGFR-bearing NSCLC is unknown.To identify the correlation between T-cell immunity and the duration of TKI response, we examined the peripheral blood mononuclear cells (PBMCs) of patients with lung cancer prior to osimertinib therapy.

1013P Utilizing a combined biomarker and therapeutic strategy to reverse TKI resistance in EGFR mutant non-small cell lung cancer

Tyrosine kinase inhibitors (TKIs) are first-line therapy for non-small-cell lung cancers (NSCLC) that harbor sensitizing mutations within the epidermal growth factor receptor (EGFR). However, resistance to TKIs such as Osimertinib remain a primary issue. Herein, we have identified the protein cell division cycle associated protein-3 (CDCA3) as a potential biomarker for TKI sensitivity and a unique therapeutic approach to target TKI resistance.

EP08.01-106 PD-1/PD-L1 Inhibitors Increase Myocardial Infarction in Osimertinib-Treated Patients with Non-Small Cell Lung Cancer

Osimertinib is now a standard of care for patients harboring T790M mutation or first-line EGFR-sensitive mutations. And it is emerging as the optimal choice for completely resected IB-IIIA non-small cell lung cancer (NSCLC) harboring EGFR mutation. While most of patients will inevitably develop resistance to osimertinib. PD-1/PD-L1 inhibitors have changed the paradigm of NSCLC therapy. Many attempts have also made with PD-1/PD-L1 inhibitors in tyrosine kinase inhibitor (TKI) resistance patients.

1171P A phase II theranostic study with osimertinib in patients with EGFR-mutated non-small cell lung cancer (NSCLC) progressing on EGFR tyrosine kinase inhibitors (TKI) and undetectable EGFR T790M (THEROS)

Personalized sequences of targeted agents instructed by the detection of resistance mechanisms by rebiopsy or liquid biopsy enable impressive survival outcomes in patients with advanced NSCLC harboring therapeutically tractable oncogenic drivers. Overcoming EGFR T790M-associated TKI resistance with osimertinib is a prime example of this approach. Limitations of current biomarkers may deny patients this treatment option. We hypothesized that early detection of metabolic response by FDG-PET identifies additional patients benefitting from sequenced osimertinib.

Association between EGFR gene mutant protein expression and T790M mutation after first-generation EGFR-TKI treatment resistance: a retrospective, single-arm clinical study.

BackgroundEpidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is an important treatment for lung adenocarcinoma patients with EGFR gene mutations. The purpose of this study was to review the efficacy of first-generation EGFR-TKIs and the incidence of T790M after first-generation TKI resistance in stage IV lung adenocarcinoma patients with positive EGFR gene mutation expression associated with EGFR mutant protein.MethodsTumor tissues were collected from stage IV lung adenocarcinoma patients with EGFR gene mutation who received first-generation EGFR-TKI targeted therapy. Patients were followed up through outpatient and inpatient systems. Immunohistochemistry was used to detect the expression of corresponding EGFR mutant protein in tumor tissues. The incidence of T790M mutation after first-generation TKI resistance and the correlation between the mutant protein and progression-free survival (PFS) after first-generation TKI treatment were investigated.ResultsT790M mutation rates were 37.93% (11/29) and 42.50% (17/40) in the EGFR mutation groups, respectively, after first-generation TKI treatment for drug resistance. In patients with exon 19 deletion, T790M mutations were found in 63.64% (7/11) of patients with positive protein expression and 22.22% (4/18) of patients with negative protein expression (P=0.026; χ2=4.974). The mutation rate of T790M after drug resistance in patients with L858R mutation was 53.57% (15/28) and 16.67% (2/12) in the protein expression-positive and negative groups, respectively (χ2=4.682, P=0.030). The variations were statistically significant.ConclusionsAfter resistance to the first-generation EGFR-TKI treatment, the occurrence of T790M mutation may be related to the expression of EGFR mutant protein in patients with EGFR gene mutation.