Co-activation of STAT3 and YES-Associated Protein 1 (YAP1) Pathway in EGFR-Mutant NSCLC

Background: The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non–small cell lung cancer (NSCLC) is limited by adaptive activation of cell survival signals. We hypothesized that both signal transducer and activator of transcription 3 (STAT3) and Src-YES-associated protein 1 (YAP1) signaling are dually activated during EGFR TKI treatment to limit therapeutic response. Methods: We used MTT and clonogenic assays, immunoblotting, and quantitative polymerase chain reaction to evaluate the efficacy of EGFR TKI alone and in combination with STAT3 and Src inhibition in three EGFR-mutant NSCLC cell lines. The Chou-Talalay method was used for the quantitative determination of drug interaction. We examined tumor growth inhibition in one EGFR-mutant NSCLC xenograft model (n = 4 mice per group). STAT3 and YAP1 expression was evaluated in tumors from 119 EGFR-mutant NSCLC patients (64 in an initial cohort and 55 in a validation cohort) by quantitative polymerase chain reaction. Kaplan-Meier and Cox regression analyses were used to assess the correlation between survival and gene expression. All statistical tests were two-sided. Results: We discovered that lung cancer cells survive initial EGFR inhibitor treatment through activation of not only STAT3 but also Src-YAP1 signaling. Cotargeting EGFR, STAT3, and Src was synergistic in two EGFR-mutant NSCLC cell lines with a combination index of 0.59 (95% confidence interval [CI] = 0.54 to 0.63) for the PC-9 and 0.59 (95% CI = 0.54 to 0.63) for the H1975 cell line. High expression of STAT3 or YAP1 predicted worse progression-free survival (hazard ratio [HR] = 3.02, 95% CI = 1.54 to 5.93, P = .001, and HR = 2.57, 95% CI = 1.30 to 5.09, P = .007, respectively) in an initial cohort of 64 EGFR-mutant NSCLC patients treated with firstline EGFR TKIs. Similar results were observed in a validation cohort. Conclusions: Our study uncovers a coordinated signaling network centered on both STAT3 and Src-YAP signaling that limits targeted therapy response in lung cancer and identifies an unforeseen rational upfront polytherapy strategy to minimize residual disease and enhance clinical outcomes

Cisplatin-Based Three Drugs Combination (NIP) as Induction and Adjuvant Treatment in Locally Advanced Non-small Cell Lung Cancer: Final Results

IntroductionThis phase III trial was conducted in non-small cell lung cancer patients with locally advanced stage II B (only T3N0) III A and III B (only T4 N0). Primary endpoint was 2-year survival; secondary were toxicity, disease-free survival, and overall survival.MethodsAfter three cycles of vinorelbine (N) 25 mg/m2 on days 1 and 5, ifosfamide/mesna (I) 3 g/m2 on day 1, cisplatin (P) (NIP), patients were treated by surgery and within 45 days were randomized to two additional cycles of NIP versus observation.ResultsMedian tumor diameter was 5.5 cm (1.2–10.6). Overall, 155 of 156 patients received chemotherapy: 133 (85%) men, median age: 59 years (35–75). Sixty-five percentage of patients were stage III A, 28% II B, and 7% III B. The study has been closed prematurely because of the low inclusion rate. After three cycles of induction in 143 assessable patients, 82 reported an objective response (57.3%) (95% CI: 48.8–65.6), with 3.5% complete response and 53.8% partial response. Relative dose intensity during neoadjuvant NIP (%) was 97, 98, and 98.5 for vinorelbine, ifosfamide/mesna, and cisplatin, respectively. Tolerance: G3 to 4 neutropenia in 3% of patients and G3 to 4 anemia in 4%; nonhematological toxicities included G3 nausea/vomiting in 11%, G3 anorexia and G3 to 4 infection in 6.5%, G3 asthenia in 10% and G3 to 4 alopecia in 25.5%. After a median of 32 days after NIP, 107 patients (69%) underwent operation with complete resection (R0) in 74% (79 of 107 patients). Downstaging (N2 to N0) after surgery was 29%. Operative mortality rate was 2.8%. Twenty-one days (median) after surgery, 79 patients were randomized to adjuvant NIP (47%) or control (53%). Tolerance of adjuvant NIP: 12.5% G3 to 4 nausea/vomiting, 19% G3 alopecia, 6% G3 infection, and G3 asthenia. Overall median survival 32.3 versus 31.8 months in the observation and NIP arms, respectively.ConclusionsNIP allows 74% of R0 with no surgery delay. The few number of randomized patients did not allow to conclude on the efficacy of adjuvant chemotherapy

Customized Treatment in Non-Small-Cell Lung Cancer Based on EGFR Mutations and BRCA1 mRNA Expression

BACKGROUND: Median survival is 10 months and 2-year survival is 20% in metastatic non-small-cell lung cancer (NSCLC) treated with platinum-based chemotherapy. A small fraction of non-squamous cell lung cancers harbor EGFR mutations, with improved outcome to gefitinib and erlotinib. Experimental evidence suggests that BRCA1 overexpression enhances sensitivity to docetaxel and resistance to cisplatin. RAP80 and Abraxas are interacting proteins that form complexes with BRCA1 and could modulate the effect of BRCA1. In order to further examine the effect of EGFR mutations and BRCA1 mRNA levels on outcome in advanced NSCLC, we performed a prospective non-randomized phase II clinical trial, testing the hypothesis that customized therapy would confer improved outcome over non-customized therapy. In an exploratory analysis, we also examined the effect of RAP80 and Abraxas mRNA levels. METHODOLOGY/PRINCIPAL FINDINGS: We treated 123 metastatic non-squamous cell lung carcinoma patients using a customized approach. RNA and DNA were isolated from microdissected specimens from paraffin-embedded tumor tissue. Patients with EGFR mutations received erlotinib, and those without EGFR mutations received chemotherapy with or without cisplatin based on their BRCA1 mRNA levels: low, cisplatin plus gemcitabine; intermediate, cisplatin plus docetaxel; high, docetaxel alone. An exploratory analysis examined RAP80 and Abraxas expression. Median survival exceeded 28 months for 12 patients with EGFR mutations, and was 11 months for 38 patients with low BRCA1, 9 months for 40 patients with intermediate BRCA1, and 11 months for 33 patients with high BRCA1. Two-year survival was 73.3%, 41.2%, 15.6% and 0%, respectively. Median survival was influenced by RAP80 expression in the three BRCA1 groups. For example, for patients with both low BRCA1 and low RAP80, median survival exceeded 26 months. RAP80 was a significant factor for survival in patients treated according to BRCA1 levels (hazard ratio, 1.3 [95% CI, 1-1.7]; P = 0.05). CONCLUSIONS/SIGNIFICANCE: Chemotherapy customized according to BRCA1 expression levels is associated with excellent median and 2-year survival for some subsets of NSCLC patients , and RAP80 could play a crucial modulating effect on this model of customized chemotherapy. TRIAL REGISTRATION: (ClinicalTrials.gov) NCT00883480

Search for gravitational-lensing signatures in the full third observing run of the LIGO-Virgo network

Gravitational lensing by massive objects along the line of sight to the source causes distortions of gravitational wave-signals; such distortions may reveal information about fundamental physics, cosmology and astrophysics. In this work, we have extended the search for lensing signatures to all binary black hole events from the third observing run of the LIGO--Virgo network. We search for repeated signals from strong lensing by 1) performing targeted searches for subthreshold signals, 2) calculating the degree of overlap amongst the intrinsic parameters and sky location of pairs of signals, 3) comparing the similarities of the spectrograms amongst pairs of signals, and 4) performing dual-signal Bayesian analysis that takes into account selection effects and astrophysical knowledge. We also search for distortions to the gravitational waveform caused by 1) frequency-independent phase shifts in strongly lensed images, and 2) frequency-dependent modulation of the amplitude and phase due to point masses. None of these searches yields significant evidence for lensing. Finally, we use the non-detection of gravitational-wave lensing to constrain the lensing rate based on the latest merger-rate estimates and the fraction of dark matter composed of compact objects

Hereditary pancreatic cancer: related syndromes and clinical perspective

Abstract Pancreatic cancer is a very aggressive disease with a poor prognosis. The majority of them are attributed to sporadic causes, especially to many modifiable risk factors such as tobacco or alcohol abuse. The principal histologic subtype of pancreatic cancer is ductal adenocarcinoma. Pancreatic neuroendocrine tumors, which constitute a more indolent entity, represent second type of pancreatic cancer in terms of incidence. Individuals with a family history of pancreatic cancer carry an increased risk of developing the disease, which may be related to an underlying hereditary component. Unfortunately, in the majority of these families the suspected germline genetic cause responsible of the disease will not be identified, but approximately in a 20% of the cases a hereditary cancer predisposition syndrome with increased risk of pancreatic cancer development can be recognized. This review will be focused on the leading hereditary cancer syndromes related to pancreatic ductal adenocarcinoma and pancreatic neuroendocrine tumors. Additionally, we will try to explain clinical aspects related to the identification of germline mutations in pancreatic cancer patients and their potential implications in oncologic treatment decisions

Association of PALB2 Messenger RNA Expression with Platinum-Docetaxel Efficacy in Advanced Non-Small Cell Lung Cancer.

Partner and localizer of BRCA2 (PALB2) is essential for homologous recombination repair. We examined mRNA levels of DNA repair genes, including partner and localizer of BRCA2 gene (PALB2), ring finger protein 8 gene (RNF8), replication timing regulatory factor 1 gene (RIF1), ATM serine/threonine kinase gene (ATM), and tumor protein p53 binding protein 1 gene (53BP1) as predictive biomarkers for cisplatin-docetaxel in the European phase III BRCA1, DNA repair associated (BRCA1)-receptor-associated protein 80 (RAP80) expression customization (BREC) phase III clinical trial (ClinicalTrials.gov identifier NCT00617656). The study was a prespecified secondary objective of the BREC trial. We assessed mRNA levels of PALB2 and four more DNA repair genes (RNF8, RIF1, ATM and 53BP1) as biomarkers in tissue from 177 patients with cisplatin-docetaxel-treated NSCLC. We examined the relationship of gene expression levels with progression-free survival, overall survival, and response. In 177 patients with NSCLC (who had a median age of 62 years and included 140 men and 91 patients with adenocarcinoma), only high PALB2 mRNA expression was predictive in the progression-free survival Cox regression analysis (hazard ratio = 0.63, 95% confidence interval: 0.42-0.83, p = 0.0080). PALB2 was also predictive of overall survival (hazard ratio = 0.68, 95% confidence interval: 0.42-0.90, p = 0.0266). Among the 158 patients evaluable for response, high PALB2 mRNA expression was predictive of response to cisplatin-docetaxel. Specifically, an objective response rate of 77% to cisplatin-docetaxel was observed for patients with high PALB2 mRNA expression compared with a rate of only 23 % for those with low PALB2 mRNA expression (p = 0.0448). High PALB2 mRNA expression identified patients with NSCLC who significantly benefited from cisplatin-docetaxel chemotherapy in the European BREC phase III clinical trial. The combination of chemotherapy with immunotherapy will become the standard of care, and a predictive marker of response to chemotherapy may accurately guide therapeutic decision making

Co-activation of STAT3 and YES-Associated Protein 1 (YAP1) Pathway in EGFR-Mutant NSCLC

The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) is limited by adaptive activation of cell survival signals. We hypothesized that both signal transducer and activator of transcription 3 (STAT3) and Src-YES-associated protein 1 (YAP1) signaling are dually activated during EGFR TKI treatment to limit therapeutic response