Integrin αvβ3 Induces HSP90 Inhibitor Resistance via FAK Activation in KRAS-Mutant Non-Small Cell Lung Cancer

Purpose HSP90 remains an important cancer target because of its involvement in multiple oncogenic protein pathways and biologic processes. Although many HSP90 inhibitors have been tested in the treatment of KRAS-mutant non–small cell lung cancer (NSCLC), most, including AUY922, have failed due to toxic effects and resistance generation, even though a modest efficacy has been observed for these drugs in clinical trials. In our present study, we investigated the novel mechanism of resistance to AUY922 to explore possible avenues of overcoming and want to provide some insights that may assist with the future development of successful next-generation HSP90 inhibitors. Materials and Methods We established two AUY922-resistant KRAS-mutated NSCLC cells and conducted RNA sequencing to identify novel resistance biomarker. Results We identified novel two resistance biomarkers. We observed that both integrin Av (ITGAv) and β3 (ITGB3) induce AUY922-resistance via focal adhesion kinase (FAK) activation, as well as an epithelial-mesenchymal transition (EMT), in both in vitro and in vivo xenograft model. mRNAs of both ITGAv and ITGB3 were also found to be elevated in a patient who had shown acquired resistance in a clinical trial of AUY922. ITGAv was induced by miR-142 downregulation, and ITGB3 was increased by miR-150 downregulation during the development of AUY922-resistance. Therefore, miR-150 and miR-142 overexpression effectively inhibited ITGAvB3-dependent FAK activation, restoring sensitivity to AUY922. Conclusion The synergistic co-targeting of FAK and HSP90 attenuated the growth of ITGAvB3-induced AUY922-resistant KRAS- mutated NSCLC cells in vitro and in vivo, suggesting that this combination may overcome acquired AUY922-resistance in KRAS-mutant NSCLC.Docto

Exploring the resistance mechanisms of second-line osimertinib and their prognostic implications using next-generation sequencing in patients with non-small-cell lung cancer

Introduction: Although osimertinib overcomes the T790M mutation acquired after traditional epidermal growth factor receptor (EGFR) gene tyrosine kinase inhibitor (TKI) treatment, resistance to osimertinib eventually occurs. We explored resistance mechanisms of second-line osimertinib and their clinical implications by comparing next-generation sequencing (NGS) results before and after resistance acquisition. Methods: We enrolled 34 patients with advanced EGFR-mutant adenocarcinoma whose biopsied tumour tissues were subjected to targeted NGS at the time of progression on osimertinib. For comparison, NGS was also performed on archived tumour tissues from each patient excised before osimertinib initiation. Results: The tumours of three patients? were observed to have transformed to small-cell carcinoma and those of two patients to squamous cell carcinoma. Among the remaining 29 patients, T790M mutations were maintained in seven patients (24.1%), including four patients (13.8%) acquiring C797S mutations and one with MET amplification. Among the 22 patients (75.9%) with T790M loss, a variety of novel mutations were identified, including KRAS mutations, PIK3CA mutations, and RET fusion, but MET amplifications (n Z 4, 18.2%) wer

Recurrence-associated gene signature in patients with stage I non-small-cell lung cancer

Recurrent gene mutations and fusions in cancer patients are likely to be associated with cancer progression or recurrence by Vogelstein et al. (Science (80-)340, 1546-1558 (2013)). In this study, we investigated gene mutations and fusions that recurrently occurred in early-stage cancer patients with stage I non-small-cell cancer (NSCLC). Targeted exome sequencing was performed to profile the variants and confirmed their fidelity at the gene and pathway levels through comparison with data for stage I lung cancer patients, which was obtained from The Cancer Genome Atlas (TCGA). Next, we identified prognostic gene mutations (ATR, ERBB3, KDR, and MUC6), fusions (GOPC-ROS1 and NTRK1-SH2D2A), and VEGF signaling pathway associated with cancer recurrence. To infer the functional implication of the recurrent variants in early-stage cancers, the extent of their selection pattern was investigated, and they were shown to be under positive selection, implying a selective advantage for cancer progression. Specifically, high selection scores were observed in the variants with significantly high risks for recurrence. Taken together, the results of this study enabled us to identify recurrent gene mutations and fusions in a stage I NSCLC cohort and to demonstrate positive selection, which had implications regarding cancer recurrence

Blood Vessel Invasion Predicts Postoperative Survival Outcomes and Systemic Recurrence Regardless of Location or Blood Vessel Type in Patients with Lung Adenocarcinoma

Background Presence of blood vessel invasion (BVI) is one of the prognostic indicators for lung cancer patients with surgical resection. However, prognostic roles of the location and the type of the involved blood vessel have not been fully evaluated yet. Patients and Methods We retrieved the data of 217 cases of surgically resected lung adenocarcinoma from Asan Medical Center. Clinicopathologic features, including BVI, were reassessed. The location (tumor center and/or periphery) and involved blood vessel types (large and/or small vessels; arteries and/or veins) of BVI were separately examined on standard hematoxylin-eosin slides and confirmed by van Gieson elastic staining. Results BVI was identified in 35% of cases (76/217), with the tumor center (intratumoral) as the location in more than half of the cases (42/76, 55.3%). The presence of BVI was significantly associated with higher pathologic stage, increased size of invasive components, frequent pleural invasion, lymphatic permeation, and spread through alveolar spaces. BVI was significantly associated with poor overall survival (OS) and recurrence-free survival (RFS) both in univariate and multivariate survival analyses [for OS, hazard ratio (HR) 1.92, 95% confidence interval (CI) 1.06-3.48, P = 0.031; for RFS, HR 2.65, 95% CI 1.64-4.28; P < 0.001]. BVI subgroups, according to location and type of the involved blood vessels, invariably displayed significantly poor RFS; however, the results for OS varied. Conclusion Regardless of their location or blood vessel type, presence of BVI is a useful predictor for postoperative survival outcomes, which should be carefully evaluated on pathologic examination

Real-world utility of next-generation sequencing for targeted gene analysis and its application to treatment in lung adenocarcinoma

Purpose This study investigated the clinical utility of next-generation sequencing (NGS) for detection of genetic alterations and its implications on treatment of lung adenocarcinoma in real-world practice. Patients and Methods Data were reviewed for 391 patients with lung adenocarcinoma who underwent NGS between March 2017 and October 2018. Formalin-fixed, paraffin-embedded archival samples were used for performing NGS targeting 382 genes, including all exons of 199 genes, 184 hotspots, and the partial introns of 8 genes often rearranged in cancer. Survival analysis was performed for stage IV disease. Results Among the 391 patients, at least one actionable mutation was identified in 294 patients (75.2%). The most commonly mutated gene was EGFR (n = 130, 33.2%), involving EGFR exon 19 deletion (n = 48, 12.3%), L858R (n = 47, 12%), and others (n = 35, 9%), followed by KRAS (n = 48, 12.3%), ALK (n = 40, 10.2%), RET (6%), MET (3%), ROS-1 (3%), and BRAF (2%) mutations. TP53 (46.9%) and CDKN2A (12.6%) mutations were common co-mutations in patients with AMs. With a median follow-up duration of 16.8 months, median overall survival was 36.8 months in patients with stage IV disease. Patients treated with the corresponding targeted therapy for AMs based on NGS reports lived significantly longer than those not treated with such therapy (p < 0.001). After multivariate analysis, targeted therapy for AM was a significantly favorable factor for survival (AM without targeted therapy vs. AM with targeted therapy, hazard ratio 2.58, 95% confidence interval 1.57-4.25; p < 0.001). Conclusion This study revealed that AMs could be comparably detected using NGS. Based on these NGS results, a suitable targeted therapy can be selected, which may improve survival in patients with lung adenocarcinoma. This NGS-based approach is useful in real-world practice to provide guidance when selecting targeted therapy

Use of Gemcitabine plus Carboplatin is Associated with Poor Outcomes in Urothelial Carcinoma Patients with Chronic Kidney Disease Stage 4-5

Abstract Purpose: This study aimed to investigate the clinical outcomes with gemcitabine-carboplatin (GCb), the standard treatment for patients with advanced urothelial carcinoma (UC) who are ineligible for cisplatin-based regimens, in advanced UC patients with a glomerular filtration rate (GFR) < 30 mL/min. Materials and methods: A retrospective cohort study involving GCb-treated advanced UC patients with GFR < 60 mL/min (n=89) was performed. Clinical outcomes were compared between subgroups with GFR < 30 mL/min and GFR ≥ 30 mL/min but < 60 mL/min. Results: Most baseline characteristics were comparable between the two subgroups. Patients with GFR < 30 mL/min had a significantly lower objective response rate (12.5%) compared to those with higher GFR levels (56.7%) (p=0.004). The number of GCb cycles was significantly lower in patients with GFR < 30 mL/min (median 2 cycles) than in those with higher GFR levels (median 6 cycles) (p=0.002). Compared to those with GFR ≥ 30 mL/min but < 60 mL/min, patients with GFR < 30 mL/min showed significantly worse progression-free survival (PFS) and overall survival (OS) (p < 0.001 for both). Further stratification of patient subgroups according to their GFR (i.e., GFR ≥ 45 mL/min but < 60 mL/min vs. GFR ≥ 30 mL/min but < 45 mL/min vs. GFR < 30 mL/min) revealed significantly different PFS and OS (p < 0.001 for both). Conclusion: The use of GCb is discouraged in advanced UC patients with GFR < 30 mL/min. Alternative therapeutic approaches with better efficacy are warranted for these patients. Keywords: Gemcitabine plus carboplatin; Glomerular filtration rate; Objective response rate; Urothelial carcinoma

Optimizing palliative chemotherapy for advanced invasive mucinous adenocarcinoma of the lung

BackgroundA primary pulmonary invasive mucinous adenocarcinoma (IMA) is a rare subtype of invasive adenocarcinoma of the lung. The prognosis of advanced IMA depending on chemotherapy regimen has not been fully investigated. Here, we compared the clinical outcomes of patients with advanced IMA treated with different palliative chemotherapies that included novel therapeutics.MethodsThis single-center retrospective study included a total of 79 patients diagnosed with IMA and treated with palliative chemotherapy. The primary outcome was the comparison of overall survival according to palliative chemotherapy type. Risk factors associated with death were evaluated as a secondary outcome.ResultsThe study cohort of 79 patients comprised 27 progressive or recurrent cases and 52 initial metastatic patients. Thirteen patients (16.5%) received targeted therapy and 18 cases (22.8%) received immunotherapy. When we compared the survival outcomes of the different treatment regimens, patients with IMA treated by immunotherapy (undefined vs. non-immunotherapy 17.0months, p<0.001) had better overall survival rates. However, there was no difference in the prognosis between the cases treated with a targeted therapy (35.6 vs. non-targeted therapy 17.0months, p=0.211). None of the conventional regimens produced a better outcome. By multivariable analysis, immunotherapy (HR 0.28; 95% CI 0.11-0.74; P=0.008) was found to be an independent prognostic factor for death.ConclusionsThis study suggests that immunotherapy for patients with advanced IMA may provide favorable outcomes than other chemotherapy options