Receptor Mutant Non-small Cell Lung Research Articles

Chitinase 3-like-1 (CHI3L1) in the pathogenesis of epidermal growth factor receptor mutant non-small cell lung cancer

Non-small cell lung cancer (NSCLC) accounts for 85 % of all lung cancers. In NSCLC, 10–20 % of Caucasian patients and 30–50 % of Asian patients have tumors with activating mutations in the Epidermal Growth Factor Receptor (EGFR). A high percentage of these patients exhibit favorable responses to treatment with tyrosine kinase inhibitors (TKI). Unfortunately, a majority of these patients develop therapeutic resistance with progression free survival lasting 9–18 months. The mechanisms that underlie the tumorigenic effects of EGFR and the ability of NSCLC to develop resistance to TKI therapies, however, are poorly understood. Here we demonstrate that CHI3L1 is produced by EGFR activation of normal epithelial cells, transformed epithelial cells with wild type EGFR and cells with cancer-associated, activating EGFR mutations. We also demonstrate that CHI3L1 auto-induces itself and feeds back to stimulate EGFR and its ligands via a STAT3-dependent mechanism(s). Highly specific antibodies against CHI3L1 (anti-CHI3L1/FRG) and TKI, individually and in combination, abrogated the effects of EGFR activation on CHI3L1 and the ability of CHI3L1 to stimulate the EGFR axis. Anti-CHI3L1 also interacted with osimertinib to reverse TKI therapeutic resistance and induce tumor cell death and inhibit pulmonary metastasis while stimulating tumor suppressor genes including KEAP1. CHI3L1 is a downstream target of EGFR that feeds back to stimulate and activate the EGFR axis. Anti-CHI3L1 is an exciting potential therapeutic for EGFR mutant NSCLC, alone and in combination with osimertinib or other TKIs.

A heterogeneous tumor immune microenvironment of uncommon epidermal growth factor receptor mutant non-small cell lung cancer.

Common epidermal growth factor receptor (EGFR) mutations are usually not considered for immunotherapy in non-small cell lung cancer (NSCLC) due to poor efficacy. However, whether uncommon EGFR mutations are suitable for immunotherapy has not been thoroughly studied. Thus, we explored the tumor immune microenvironment (TME) features in uncommon EGFR mutant NSCLC. In this study, a total of 41 patients with EGFR mutations were included, the majority (85.4%) of whom were stage I. Among them, 22 patients harbored common mutations, while 19 patients presented with uncommon mutations. Compared with common mutations, uncommon mutations exhibited more infiltrating T cells and fewer M2 macrophages, upregulated expression of antigen processing and a presentation pathway. Unsupervised clustering based on the mIF profile identified two classes with heterogeneous TME in uncommon mutations. Class 1 featured the absence of PD-1+ cytotoxic T cell infiltration, and class 2 displayed a hotter TME because of the downregulated expression of hypoxia (p < 0.001), oxidative phosphorylation (p = 0.009), and transforming growth factor beta signaling (p = 0.01) pathways as well as increased expression of CTLA4 (p = 0.001) and PDCD1 (p = 0.004). The association of CTLA4 and PDCD1 with TME profiles was validated in a TCGA lung adenocarcinoma cohort with uncommon EGFR mutations. Our study reveals the distinct and heterogeneous TME features in uncommon EGFR mutant NSCLC.

Brain exposure of osimertinib in patients with epidermal growth factor receptor mutation non-small cell lung cancer and brain metastases: A positron emission tomography and magnetic resonance imaging study.

Brain metastases (BMs) are associated with poor prognosis in epidermal growth factor receptor mutation-positive (EGFRm) non-small cell lung cancer (NSCLC). Osimertinib is a third-generation, irreversible, EGFR-tyrosine kinase inhibitor that potently and selectively inhibits EGFR-sensitizing and T790M resistance mutations with efficacy in EGFRm NSCLC including central nervous system (CNS) metastases. The open-label phase I positron emission tomography (PET) and magnetic resonance imaging (MRI) study (ODIN-BM) assessed [11 C]osimertinib brain exposure and distribution in patients with EGFRm NSCLC and BMs. Three dynamic 90-min [11 C]osimertinib PET examinations were acquired together with metabolite-corrected arterial plasma input functions at: baseline, after first oral osimertinib 80 mg dose, and after greater than or equal to 21 days of osimertinib 80 mg q.d. treatment. Contrast-enhanced MRI was performed at screening and after 25-35 days of osimertinib 80 mg q.d.; treatment effect was assessed per CNS Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and per volumetric changes in total BM using a novel analysis approach. Four patients (aged 51-77 years) completed the study. At baseline, ~1.5% injected radioactivity reached the brain (IDmax[brain] ) 22 min (median, Tmax[brain] ) after injection. Total volume of distribution (VT ) in whole brain was numerically higher compared with the BM regions. After a single oral osimertinib 80 mg dose, there was no consistent decrease in VT in whole brain or BMs. After greater than or equal to 21 days' daily treatment, VT in whole brain and BMs were numerically higher versus baseline. MRI revealed 56%-95% reduction in total BMs volume after 25-35 days of osimertinib 80 mg q.d. treatment. The [11 C]osimertinib crossed the blood-brain and brain-tumor barriers and had a high, homogeneous brain distribution in patients with EGFRm NSCLC and BMs.

Neoadjuvant Osimertinib Followed by Sequential Definitive Radiation Therapy and/or Surgery in Stage III Epidermal Growth Factor Receptor–Mutant Non-Small Cell Lung Cancer: An Open-Label, Single-Arm, Phase 2 Study

The treatment for unresectable, locally advanced stage III non-small cell lung cancer (NSCLC) is concurrent chemoradiation therapy (CRT) followed by consolidation durvalumab. This study aimed to evaluate the benefit of neoadjuvant osimertinib as an alternative therapy to this approach with the aim of reducing the radiation field. This investigation was a nonrandomized, open-label, single-arm, phase 2, prospective, proof-of-concept study. Eligible patients were classified as having treatment-naïve, nonoperable, stage III epidermal growth factor receptor-mutant NSCLC. Patients received 80 mg of oral osimertinib daily for 12 weeks before definitive radiation therapy (RT) and/or surgery. The response was assessed at weeks 6 and 12. For responders, sequential definitive RT and/or surgery were planned. Nonresponders were started on standard CRT. After RT ± surgery or CRT, patients were followed for 2 years without adjuvant therapy. The primary endpoint was the objective response rate (ORR), with September 20, 2022, set as the cut-off for data collection. Secondary endpoints were safety and the gross tumor volume (GTV), planned tumor volume (PTV), and the percentage of total lung volume minus GTV exceeding 20 Gy (V20%) before versus after osimertinib. Exploratory analyses included assessments of the presence of plasma circulating tumor-free DNA (ctDNA) before osimertinib treatment, at weeks 6 and 12, at the end of RT, and 6 weeks post-RT. Twenty-four patients were included (19 women; median age, 73 years; range, 51-82 years). Nineteen of 24 had never smoked, 20 of 24 had adenocarcinoma, 16 of 24 had exon 19 deletions, and 8 of 24 had exon 21 mutations. Participants had stage IIIA (10), IIIB (9), or IIIC (5) disease. Three patients were excluded from the analysis (1 dropped out and 2 were still undergoing osimertinib treatment at the cut-off date). The ORR to induction osimertinib was 95.2% (17 partial response, 3 complete response, and 1 progressive disease). After induction osimertinib, 13 of 20 patients were definitively radiated, 3 of 20 underwent surgery, and 5 of 20 were excluded. Four patients were restaged as stage IV (contralateral ground-glass opacities responded to osimertinib), and 1 patient withdrew informed consent. Three patients underwent surgery, one of whom was treated with RT. Two patients achieved pT1aN0, and one achieved pathologic complete response. The median GTV, PTV, and V20% before osimertinib treatment were 47.4 ± 76.9 cm3 (13.5-234.9), 227.0 ± 258.8 cm3 (77.8-929.2), and 27.1 ± 16.4% (6.2-60.3), respectively. The values after osimertinib treatment were 27.5 ± 42.3 cm3 (2.99-137.7; -48 ± 20%; P=.02), 181.9 ±198.4 cm3 (54-718.1; -31 ± 20%; P=.01), and 21.8 ± 11.7% (9.1-44.15; -24 ± 40%; P=.04), respectively. PTV/GTV/V20% reduction was associated with tumor size and central location. The median follow-up time was 28.71 months (range, 0.4-45.1 months), and median disease-free survival was not reached (mean, 30.59; standard error, 3.94; 95% confidence interval, 22.86-38.31). ctDNA was detected in 5 patients; 4 of 5 were positive for ctDNA at baseline and became negative during osimertinib induction but were again positive after osimertinib treatment was terminated. Interestingly, 3 patients who were ctDNA negative at baseline became weakly positive after RT and then were negative at follow-up. No significant adverse events were reported during the osimertinib or radiation phases. Neoadjuvant osimertinib therapy is feasible in patients with stage III lung cancer NSCLC, followed by definitive radiation and/or surgery, with an ORR of 95.2% and an excellent safety profile. Osimertinib induction for 12 weeks before definitive radiation (chemo-free) significantly reduced the radiation field by nearly 50% with a linear association with tumor size. Further studies are needed to test this chemo-free approach for long-term outcomes before practices are changed.

Final report on plasma ctDNA T790M monitoring during EGFR-TKI treatment in patients with EGFR mutant non-small cell lung cancer (JP-CLEAR trial).

Osimertinib is active against T790M-positive epidermal growth factor receptor mutant non-small cell lung cancer. We enrolled 122 sensitive epidermal growth factor receptor mutant non-small cell lung cancer patients who were planned to receive or were receiving first-/second-generation epidermal growth factor receptor tyrosine kinase inhibitors without disease progression and monitored plasma T790M every 1–2 months using the cobas® EGFR Mutation Test v2. We previously reported the concordance between T790M status in plasma and tissue. This is the final report on the sensitivity of plasma T790M and the efficacy of sequential osimertinib. The sensitivity was 21.1% (95% confidence interval: 6.1–45.6%). The best overall response was 25.0% (95% confidence interval: 9.8–46.7) in the plasma T790M-positive group and 28.6% (95% confidence interval: 8.4–58.1) in the plasma T790M-negative but tissue T790M-positive group. Median progression-free survival was 7.9 months (95% confidence interval: 4.7–17.5) for the former and 4.4 months (95% confidence interval: 3.0–N.E.) for the latter, with no statistically significant difference (P = 0.74).

Clinical Value of Upfront Cranial Radiation Therapy in Osimertinib-Treated Epidermal Growth Factor Receptor–Mutant Non-Small Cell Lung Cancer With Brain Metastases

As a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimertinib has a powerful ability to penetrate the blood-brain barrier and a high potency for controlling brain metastases (BMs) from EGFR-mutant non-small cell lung cancer (NSCLC). The clinical value of cranial radiation therapy in osimertinib-treated NSCLC with BMs remains largely unknown. Patients with NSCLC and BMs and receiving osimertinib treatment as the standard of care were retrospectively enrolled from 2 institutions. Cranial radiation therapy (RT; whole-brain radiation therapy [WBRT] or/and stereotactic radiosurgery [SRS]) performed before disease progression (PD) to osimertinib was categorized as upfront cranial radiation therapy (ucRT group), excluding those treatments performed during prior EGFR-TKI treatment. Overall survival (OS), progression-free survival (PFS), and the time to intracranial progression (iTTP) were compared between the 2 groups, with adjustment by covariates in propensity-score matched (PSM) analyses. The state of having 1 to 3 BM lesions, with a maximal size of ≤3 cm, was defined as having oligo-BM; otherwise; the cases were defined as having multiple BMs. Of the 205 patients enrolled, osimertinib was used as first-line therapy in 74 and second-line therapy in 131. There were 48 patients who received ucRTs, including WBRT in 24 and SRS in 24. All patients with oligo-BM in the ucRT group received SRS alone (n=17), whereas most (n=28; 90.3%) patients with multiple BMs received WBRT. Failure pattern analyses indicated that in the non-ucRT group, 40.2% of the initial PD involved the brain and 76.9% of the cranial PD involved the original sites, indicating the potential roles of ucRT. Indeed, the iTTP was significantly prolonged (P=.010) in the ucRT group among the whole population. In the PSM oligo-BM cohort, the ucRT group showed superior PFS (P=.033) and OS (P=.026) compared with the non-ucRT group, and the differences remained after multivariate Cox analyses. No such differences were observed in the subpopulation with multiple BMs. In osimertinib-treated NSCLC patients with BMs, oligo-BM status could be used as a potential factor to select patients for upfront cranial RT. Further investigation by well-designed clinical trials is warranted.

Efficacy of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in the Adjuvant Setting for Patients with Resected Epidermal Growth Factor Receptor Mutant Non-Small Cell Lung Cancer: A Meta-Analysis with 11 Trials

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have recently become the standard first-line therapy for advanced non-small cell lung cancer (NSCLC) patients harboring EGFR mutations. This study aimed to define the role of EGFR-TKI treatment in the adjuvant setting of patients with resected EGFR-mutant NSCLC. Methods: Three online databases (PubMed, Embase, and the Cochrane Library) were used to conduct systematic research to search for studies published before June 1, 2020. The disease-free survival (DFS) and overall survival (OS) of patients with resected EGFR-mutant NSCLC after radical surgery treated with EGFR-TKIs versus non-EGFR-TKIs in the adjuvant setting were compared. Based on rigorous self-defined inclusion and exclusion criteria, studies were selected, and a meta-analysis was performed using hazard rate (HR) and 95% CIs as effective measures. Results: Eleven studies, published between 2011 and 2020, with a total of 1,900 patients, were included in this meta-analysis. EGFR-TKI treatment showed a significant beneficial effect on DFS (HR 0.42; 95% CI 0.31–0.57) and OS (HR 0.62; 95% CI 0.45–0.86) for patients with resected EGFR-mutant NSCLC after radical resection in the adjuvant setting. Conclusion: Our meta-analysis results suggested that EGFR-TKI treatment improved the DFS and OS of completely resected patients with EGFR-mutant NSCLC compared with non-EGFR-TKI treatment in the adjuvant setting. In the future, our conclusion should be confirmed by additional large-scale and well-designed clinical trials.

Cost-effectiveness analysis of tyrosine kinase inhibitors (erlotinib, gefitinib, afatinib and osimertinib) as first-line therapy for epidermal growth factor receptor-mutated advanced non-small cell lung cancer

Cost-effectiveness analysis of tyrosine kinase inhibitors (erlotinib, gefitinib, afatinib and osimertinib) as first-line therapy for epidermal growth factor receptor-mutated advanced non-small cell lung cancer

Stereotactic Body Radiotherapy Combined with Targeted Therapy in Oligoprogressive or Primary Epidermal Growth Factor Receptor Mutated Non-Small Cell Lung Cancer

Stereotactic Body Radiotherapy Combined with Targeted Therapy in Oligoprogressive or Primary Epidermal Growth Factor Receptor Mutated Non-Small Cell Lung Cancer

The efficacy and safety of first-line therapy for the epidermal growth factor receptor mutant non-small cell lung cancer in older versus younger patients: A pooled analysis of two randomized controlled trials

Background: There is a scarcity of data to guide the management of older patients with cancer. We therefore conducted this study to compare the outcomes and toxicities in older versus younger patients with an epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC).Patients and Methods: For this pooled analysis, we utilized the individual patient databases of two prospective, first-line Phase III randomized controlled trials in patients with EGFR-mutant advanced NSCLC. The therapies in the two trials included gefitinib alone, pemetrexed/carboplatin, followed by maintenance pemetrexed and the combination of gefitinib with pemetrexed/carboplatin chemotherapy. We evaluated the progression-free survival (PFS) and overall survival (OS) of older patients (=/> 60 years) as compared to younger patients. Grade 3 or worse adverse events were also compared.Results: A total of 640 patients were included in this analysis, of which 156 (24.3%) were 60 years or older. The median PFS with first-line therapy was 8.5 months (95% confidence interval [CI], 7.8–9.2) in younger versus 9 months (95% CI, 6.7–11.4) in older patients (hazard ratio [HR], 2.3; 95% CI, 0.8–6.7; P = 0.575). The median OS of younger patients was 23.2 months (95% CI, 20.6–25.6) compared to 19 months (95% CI, 14.2–23.7) in older patients (HR, 1.18; 95 CI, 0.89–1.54, P = 0.234). On comparing older with younger patients for various known prognostic factors, there was no difference in OS based on any of the factors. On comparing the toxicities between the younger and older patients in the combination group, there was no difference in Grade 3 or 4 toxicities between younger and older patients except higher incidence of diarrhea in older patients (24.4% versus 9.3%, P = 0.010).Conclusions: In patients with EGFR-mutated NSCLC, similar survival and toxicities were found in patients aged 60 years or older as compared to younger patients with Eastern Cooperative Oncology Group Performance Status of 0–2, except for a higher incidence of diarrhea in older patients.

Tyrosine Kinase Inhibitor versus Physician Choice Chemotherapy in Second-Line Epidermal Growth Factor Receptor Mutation Non-Small Cell Lung Cancer: Post hoc Analysis of Randomized Control Trial

Abstract Background: There is a paucity of prospective data for patients who progressed after first-line tyrosine kinase inhibitor (TKI) or pemetrexed doublet among epidermal growth factor receptor (EGFR) mutation-positive metastatic non-small cell lung cancer (NSCLC). Aim: The aim of the study was to evaluate the outcome of second-line therapy in patients who progressed on TKI or pemetrexed doublet in EGFR mutation-positive NSCLC. Objective: The objective of the study was to calculate response rates, progression-free survival (PFS), and overall survival (OS) of patients receiving second-line therapy in EGFR mutation NSCLC. Materials and Methods: Post hoc analysis of second-line therapy among patients enrolled in randomized control trial comparing TKI versus pemetrexed doublet in EGFR mutation NSCLC. Kaplan–Meir statistics were used for PFS and OS. Impact of variables was measured with Log-rank test. Results: One hundred and eighty-seven patients who progressed on first-line therapy and received second-line agents were analyzed. Male:female: 110 (56.3%):77 (41.2%). One hundred and thirteen patients received gefitinib, while 74 received chemotherapy. Response rate (complete response + partial response) was 53% versus 24% in gefitinib versus chemotherapy group (RECIST v1.1). PFS was 7.4 months versus 4.4 months (P = 0.001), while OS was 14 months versus 9.7 months (P = 0.007), in gefitinib versus chemotherapy group, respectively. Response to TKI significantly improves PFS (10.8 months vs. 3.9 months, P = 0.001) and OS (21.4 months vs. 8.9 months, P = 0.03). Rash, pruritus, dry skin, fatigue, diarrhea, and paronychia were common toxicities of TKI. Conclusion: Second-line TKI improves outcome in EGFR mutation-positive NSCLC who progressed after first-line chemotherapy. Response to therapy, whether with TKI or chemotherapy, favorably impacts outcomes.

Impact of Deferring Radiation Therapy in Patients With Epidermal Growth Factor Receptor–Mutant Non-Small Cell Lung Cancer Who Develop Brain Metastases

Toperform a retrospective analysis of patients with epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma who developed brain metastases (BM) to evaluate our hypothesis that the use of upfront EGFR-tyrosine kinase inhibitors (TKIs), and deferral of radiation therapy (RT), would result in inferior intracranial progression-free survival but similar overall survival (OS). Of 202 patients diagnosed with EGFR-mutant NSCLC between July 1, 2008, and December 31, 2014, 71 developed BM. Twenty-one patients were excluded owing to prior EGFR-TKI use, EGFR-TKI resistance mutation, failure to receive EGFR-TKI after whole-brain radiation therapy (WBRT)/stereotactic radiosurgery (SRS) or <6months' follow-up. Of the remaining 50 patients, 17 received upfront EGFR-TKI followed by SRS or WBRT, 17 WBRT then EGFR-TKI, and 16 SRS followed by EGFR-TKI. Disease-specific-graded prognostic assessment was similar among all 3 groups. The median OS was longer in the upfront RT group compared with the upfront EGFR-TKI group (34.1 vs 19.4months; P=.01). On subgroup analysis, the SRS group had longer OS than the upfront EGFR-TKI group (58.4 vs 19.4months; P=.01), but the WBRT group did not (29.9 vs 19.4months; P=.09). Intracranial progression-free survival was improved in patients receiving upfront RT compared with those receiving upfront EGFR-TKI (37.9 vs 10.6months; P<.001). The present study suggests that the use of upfront EGFR-TKI, and the deferral of SRS or WBRT, may result in inferior OS in patients with EGFR-mutant NSCLC who develop brain metastases. A prospective, multi-institutional, randomized trial of upfront EGFR-TKI with RT at intracranial progression versus upfront RT followed by EGFR-TKI is urgently needed.

Efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors for patient with leptomeningeal metastasis of epidermal growth factor receptor mutant non-small cell lung cancer

Efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors for patient with leptomeningeal metastasis of epidermal growth factor receptor mutant non-small cell lung cancer

Baseline and Trend of Lymphocyte-to-Monocyte Ratio as Prognostic Factors in Epidermal Growth Factor Receptor Mutant Non-Small Cell Lung Cancer Patients Treated with First-Line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors.

BackgroundPatients with early-stage lung cancer who have a high baseline lymphocyte-to-monocyte ratio (LMR) have a favorable prognosis. However, the prognostic significance of LMR in patients with advanced-stage EGFR-mutant non-small cell lung cancer (NSCLC) receiving first-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) has not been established. We conducted a retrospective analysis to investigate the influence of LMR on clinical outcomes including progression-free survival (PFS) and overall survival (OS) in EGFR-mutant patients with NSCLC.Materials and MethodsOf 1310 lung cancer patients diagnosed between January 2011 and October 2013, 253 patients receiving first-line EGFR-TKIs for EGFR-mutant NSCLC were included. The cut-off values for baseline and the 1-month-to-baseline ratio of LMR (MBR), determined by using receiver operating characteristic curves, were 3.29 and 0.63, respectively. Patients were divided into 3 prognostic groups: high LMR and MBR, high LMR or MBR, and low LMR and MBR.ResultsThe mean patient age was 65.2 years, and 41% were men. The median PFS and OS were 10.3 and 22.0 months, respectively. The PFS in patients with high LMR and MBR, high LMR or MBR, and low LMR and MBR were 15.4, 7.1, and 2.0 months, respectively (p < 0.001), whereas the OS were 32.6, 13.7, and 5.1 months, respectively (p < 0.001).ConclusionA combination of baseline and trend of LMR can be used to identify patients with a high mortality risk in EGFR-mutant NSCLC patients receiving first-line EGFR-TKIs.

The gefitinib dose reduction on survival outcomes in epidermal growth factor receptor mutant non-small cell lung cancer.

Gefitinib is safe for the treatment of non-small cell lung cancer (NSCLC), but some patients experience toxicities and require dose reduction. The purpose of this study was to evaluate the effect of gefitinib dose reduction on survival. We retrospectively analyzed 263 patients with NSCLC harboring sensitive epidermal growth factor receptor (EGFR) mutation. All patients had recurred or metastatic disease and received gefitinib 250mg daily as palliative chemotherapy. Of the 263 patients, 23 had gefitinib dose reduction due to toxicities (1 due to mucositis, 5 due to skin rash, 11 due to hepatotoxicity and 6 for both skin and hepatotoxicity). In the dose reduction group, the mean dose intensity was 0.84 (range 0.48-0.98). Patients with dose reduction showed significantly prolonged progression-free survival (PFS) and overall survival (OS) compared to those receiving the standard dose (median PFS: 14.0 vs. 10.6months, P=0.042, median OS: 54.5 vs. 29.6, P=0.020). In multivariate analysis, the effect of dose reduction was not significantly associated with prolonged PFS [hazard ratio (HR) 0.619, 95% confidence interval (CI) 0.357-1.073, P=0.085], or OS (HR 0.625, 95% CI 0.287-1.362, P=0.237). However, patients receiving low-dose gefitinib tended to have superior survival outcomes compared to those receiving standard-dose gefitinib. The patients experiencing gefitinib dose reduction or short-term treatment interruption due to toxicities did not show inferior survival, compared to those receiving full dose of gefitinib in NSCLC patients with EGFR mutation.

26 Treatment and outcome in epidermal growth factor receptor mutant non-small cell lung cancer: A retrospective audit across four NHS trusts

26 Treatment and outcome in epidermal growth factor receptor mutant non-small cell lung cancer: A retrospective audit across four NHS trusts

Molecular mechanism of erlotinib resistance in epidermal growth factor receptor mutant non-small cell lung cancer cell line H1650

背景与目的表皮生长因子受体（epidermal growth factor receptor, EGFR）高表达和突变与40%左右的肺癌有关，已成为靶向治疗药物研究热点；随着Gefitinib和Erlotinib作为EGFR酪氨酸激酶抑制剂（tyrosine kinase inhibitor, TKI）代表药物应用于临床，继而产生的耐药现象亦成为临床一大难题，部分耐药机制仍不清楚。本研究探讨非小细胞肺癌（non-small cell lung cancer, NSCLC）细胞系H1650耐药机制。方法选用real-time RT-PCR检测EGFR野生型NSCLC细胞系中EGFR mRNA表达水平；MTT检测癌细胞对Erlotinib的药物敏感性；Western blot检测EGFR突变NSCLC细胞系突变情况和Erlotinib及PI3K抑制剂（LY294002）对EGFR突变型NSCLC细胞下游信号蛋白磷酸化水平的影响。结果EGFR野生型细胞系中，EGFR mRNA表达水平高低不一，但均对Erlotinib耐药；EGFR突变型细胞系中，HCC827和H1650为同种突变类型，HCC827对Erlotinib敏感，H1650则相对耐药；检测显示，H1650细胞中PTEN表达缺失，给予Erlotinib和LY294002处理后，HCC827中p-AKT明显被抑制，但H1650中p-AKT下调不明显。结论在NSCLC细胞系中，Erlotinib药物敏感性与EGFR的mRNA表达高低无关，但与EGFR的突变类型有关；H1650对Erlotinib相对耐药可能与PTEN缺失导致的p-AKT持续活化有关。