CXCR7 Reactivates ERK Signaling to Promote Resistance to EGFR Kinase Inhibitors in NSCLC

Abstract Although EGFR mutant–selective tyrosine kinase inhibitors (TKI) are clinically effective, acquired resistance can occur by reactivating ERK. We show using in vitro models of acquired EGFR TKI resistance with a mesenchymal phenotype that CXCR7, an atypical G protein-coupled receptor, activates the MAPK–ERK pathway via β-arrestin. Depletion of CXCR7 inhibited the MAPK pathway, significantly attenuated EGFR TKI resistance, and resulted in mesenchymal-to-epithelial transition. CXCR7 overexpression was essential in reactivation of ERK1/2 for the generation of EGFR TKI–resistant persister cells. Many patients with non–small cell lung cancer (NSCLC) harboring an EGFR kinase domain mutatio…

15P A pivotal multicenter translational research project on malignant pleural mesothelioma (MPM): Preliminary results

Tratamiento neoadyuvante del cáncer de mama operable

Preoperative or neoadjuvant systemic treatment refers to either the first postdiagnosis systemic treatment that a patient receives or indicates that additional subsequent therapy is intended. Randomized controlled clinical trials have shown that preoperative systemic treatment offers the same disease free survival and overall survival benefits as does adjuvant systemic treatment. Neoadjuvant therapy has been found to increase the breast-conserving surgery rate. This therapy also allows to evaluate the primary tumor response to chemotherapy. Additionally, on the basis of the biologic characteristics of a tumor and differences in the response to systemic treatment, primary systemic treatment …

Abstract LB-099: Metabolic vulnerabilities of mesenchymal-like EGFR-mutant NSCLC cells with acquired resistance to tyrosine kinase inhibitors

Abstract Despite the availability of the effective targeted therapies in lung cancer, such as EGFR tyrosine kinase inhibitors (TKIs), drug tolerance and acquired resistance are two common problems that negatively impact lung cancer patient survival. Consequently it is important to understand the molecular basis of the drug tolerance and resistance so that we could formulate effective strategies to ameliorate the efficacy of existing drug and to suppress the emergence of drug resistance. A burgeoning body of literature demonstrated that epigenetic changes by the methylation of DNA and histones are critical in acquired drug resistance, especially in those cancer cells with stem cell-like prop…

Mutational analysis ofBRCA1andBRCA2in Mediterranean Spanish women with early-onset breast cancer: Identification of three novel pathogenic mutations

In Spain, the contribution of BRCA mutations to the population incidence of early-onset breast cancer was unknown. We carried out a mutational analysis of the BRCA1 and BRCA2 genes in 124 Spanish women diagnosed with breast cancer before the age 41 and who were not selected for a family history of this disease. The genetic study was performed by PCR-SSCP analysis and DNA sequencing. We identified 6 pathogenic BRCA mutations in 7 unrelated probands (5.6%; 95% CI=2.3% to 11.3%): 1 BRCA1 (c.2080delA) and 5 BRCA2 (p.Y3006X, p.Q1994X, c.9204_9217del14, c.9254_9258del5 and c.295+2T>C). Three out of 6 mutations were novel (BRCA2 p.Y3006X, c.9204_9217del14, and c.295+2T>C), and two further mutation…

Ten-year assessment of a cancer fast-track programme to connect primary care with oncology: reducing time from initial symptoms to diagnosis and treatment initiation.

Background Cancer is the second leading cause of mortality worldwide. Integrating different levels of care by implementing screening programmes, extending diagnostic tools and applying therapeutic advances may increase survival. We implemented a cancer fast-track programme (CFP) to shorten the time between suspected cancer symptoms, diagnosis and therapy initiation. Patients and methods Descriptive data were collected from the 10 years since the CFP was implemented (2009-2019) at the Clinico-Malvarrosa Health Department in Valencia, Spain. General practitioners (GPs), an oncology coordinator and 11 specialists designed guidelines for GP patient referral to the CFP, including criteria for br…

Final results of RENO study: Randomized phase II of oral vinorelbine or etoposide with cisplatin and chemo-radiation in stage III NSCLC. SLCG 10/02.

e20521Background: This study aims to compare efficacy and safety of two widely used combinations of cisplatin (P) in this setting: as etoposide (E) and vinorelbine. This last, in its oral formulati...

LungBEAM: A prospective multicenter study to monitor stage IV NSCLC patients with EGFR mutations using BEAMing technology

Abstract Objectives The aim of LungBEAM was to determine the value of a novel epidermal growth factor receptor (EGFR) mutation test in blood based on BEAMing technology to predict disease progression in advanced non‐small cell lung cancer (NSCLC) patients treated with first‐ or second‐generation EGFR‐tyrosine kinase inhibitors (EGFR‐TKIs). Another goal was to monitor the dynamics of EGFR mutations, as well as to track EGFR exon 20 p.T790M (p.T790M) resistance during treatment, as critical indicators of therapeutic efficacy and patient survival. Methods Stage IV NSCLC patients with locally confirmed EGFR‐TKI sensitizing mutations (ex19del and/or L858R) in biopsy tissue who were candidates to…

In the literature: December 2019

The introduction of new high-throughput technologies in oncology and the need to apply precision medicine for cancer patients has led to the detection of several molecular alterations. Among them, activating mutations of ERBB2 have been reported in many solid tumours. In the last years, several clinical trials with covalent tyrosine kinase inhibitors (TKIs) for ERBB2 mutant cancers have been conducted, with different results among several cancer types. In the SUMMIT trial, neratinib was most effective in breast cancer patients, with the majority of responders having tumours with L755S, V777L, or L869R ERBB2 mutations.1 In an elegant article published in C ancer C ell by Robichaux et al ,2 d…

In the literature: February 2019

Malignant pleural mesothelioma (MPM) is a rare and lethal cancer associated to asbestos exposure. Currently, the pemetrexed and cisplatin combination chemotherapy remains the only approved treatment. In the last 5 years, a growing knowledge on mesothelioma pathobiology has translated into the development of multiple novel therapeutic strategies.1 One of the largest reports of comprehensive genomic profiling of MPM was conducted by Bueno and colleagues. Using RNA-seq data, they identified four distinct molecular subtypes, and through exome analysis, they found that BAP1 , NF2 , TP53 , SETD2 , DDX3X , ULK2 , RYR2 , CFAP45 , SETDB1 and DDX51 were significantly mutated.2 In an article recently …