BID expression determines the apoptotic fate of cancer cells after abrogation of the spindle assembly checkpoint by AURKB or TTK inhibitors.

Background: Drugs targeting the spindle assembly checkpoint (SAC), such as inhibitors of Aurora kinase B (AURKB) and dual specific protein kinase TTK, are in different stages of clinical development. However, cell response to SAC abrogation is poorly understood and there are no markers for patient selection.

Methods: A panel of 53 tumor cell lines of different origins was used.

Multiplex Analysis of CircRNAs from Plasma Extracellular Vesicle-Enriched Samples for the Detection of Early-Stage Non-Small Cell Lung Cancer.

Background: The analysis of liquid biopsies brings new opportunities in the precision oncology field. Under this context, extracellular vesicle circular RNAs (EV-circRNAs) have gained interest as biomarkers for lung cancer (LC) detection. However, standardized and robust protocols need to be developed to boost their potential in the clinical setting.

Combined FGFR and Akt pathway inhibition abrogates growth of FGFR1 overexpressing EGFR-TKI-resistant NSCLC cells.

EGFR tyrosine kinase inhibitor (TKI) resistance in non-small cell lung cancer (NSCLC) patients is inevitable. Identification of resistance mechanisms and corresponding targeting strategies can lead to more successful later-line treatment in many patients. Using spectrometry-based proteomics, we identified increased fibroblast growth factor receptor 1 (FGFR1) expression and Akt activation across erlotinib, gefitinib, and osimertinib EGFR-TKI-resistant cell line models.

Anti-epidermal growth factor vaccine antibodies increase the antitumor activity of kinase inhibitors in ALK and RET rearranged lung cancer cells.

Advanced NSCLC patients harboring EML4-ALK and CCDC6-RET rearrangements derive benefit from treatment with ALK and RET TKIs but not immune checkpoint inhibitors. New immunotherapeutic approaches, such as immunization against growth factors, can be of particular interest for combination treatment in these patients. Here, we investigated the effects of anti-EGF antibodies generated by vaccination (anti-EGF VacAbs), TKIs and combinations in EML4-ALK and CCDC6-RET NSCLC cell lines.

Detection of somatic mutations in peritoneal lavages and plasma of endometrial cancer patients: A proof-of-concept study.

Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries. Although most patients are diagnosed at early stages, 15-20% will relapse despite local treatment. Presently, there are no reliable markers to identify patients with worse outcomes who may benefit from adjuvant treatments, such as chemotherapy, and liquid biopsies may be of use in this setting.

Characterising acquired resistance to erlotinib in non-small cell lung cancer patients.

: The therapy of patients with lung adenocarcinoma has significantly changed after the discovery of epidermal growth factor receptor (EGFR) mutations. EGFR mutations occur in 10-15% of Caucasian lung cancer patients and are associated with favorable outcome to orally administered EGFR tyrosine kinase inhibitors (TKIs), like erlotinib. However, as soon as the tumor cells are under the pressure of the specific inhibitor, compensatory signaling pathways are activated and resistance emerges.

AURKB as a target in non-small cell lung cancer with acquired resistance to anti-EGFR therapy.

Non-small cell lung cancer (NSCLC) tumors harboring mutations in EGFR ultimately relapse to therapy with EGFR tyrosine kinase inhibitors (EGFR TKIs). Here, we show that resistant cells without the p.T790M or other acquired mutations are sensitive to the Aurora B (AURKB) inhibitors barasertib and S49076.

Prospective analysis of liquid biopsies of advanced non-small cell lung cancer patients after progression to targeted therapies using GeneReader NGS platform.

Background: In a significant percentage of advanced non-small cell lung cancer (NSCLC) patients, tumor tissue is unavailable or insufficient for genetic analyses at time to progression. We prospectively analyzed the appearance of genetic alterations associated with resistance in liquid biopsies of advanced NSCLC patients progressing to targeted therapies using the NGS platform.

Methods: A total of 24 NSCLC patients were included in the study, 22 progressing to tyrosine kinase inhibitors and two to other treatments.

Anti-Epidermal Growth Factor Vaccine Antibodies Enhance the Efficacy of Tyrosine Kinase Inhibitors and Delay the Emergence of Resistance in EGFR Mutant Lung Cancer Cells.

Introduction: Mutations in EGFR correlate with impaired response to immune checkpoint inhibitors and the development of novel immunotherapeutic approaches for EGFR mutant NSCLC is of particular interest. Immunization against epidermal growth factor (EGF) has shown efficacy in a phase III trial including unselected NSCLC patients, but little was known about the mechanisms involved in the effects of the anti-EGF antibodies generated by vaccination (anti-EGF VacAbs) or their activity in tumor cells with EGFR mutations.

Methods: The EGFR-mutant, NSCLC cell lines H1975, and PC9, together with several gefitinib and osimertinib-resistant cells derived from PC9, were treated with anti-EGF VacAbs and/or EGFR tyrosine kinase inhibitors (TKIs).

Convergent Akt activation drives acquired EGFR inhibitor resistance in lung cancer.

Non-small-cell lung cancer patients with activating epidermal growth factor receptor (EGFR) mutations typically benefit from EGFR tyrosine kinase inhibitor treatment. However, virtually all patients succumb to acquired EGFR tyrosine kinase inhibitor resistance that occurs via diverse mechanisms. The diversity and unpredictability of EGFR tyrosine kinase inhibitor resistance mechanisms presents a challenge for developing new treatments to overcome EGFR tyrosine kinase inhibitor resistance.

Liquid Biopsy in Non-Small Cell Lung Cancer.

Liquid biopsy analyses are already incorporated in the routine clinical practice in many hospitals and oncology departments worldwide, improving the selection of treatments and monitoring of lung cancer patients. Although they have not yet reached its full potential, liquid biopsy-based tests will soon be as widespread as "standard" biopsies and imaging techniques, offering invaluable diagnostic, prognostic, and predictive information. This review summarizes the techniques available for the isolation and analysis of circulating free DNA and RNA, exosomes, tumor-educated platelets, and circulating tumor cells from the blood of cancer patients, presents the methodological challenges associated with each of these materials, and discusses the clinical applications of liquid biopsy testing in lung cancer.

cfDNA analysis from blood in melanoma.

Testing of tumor tissue remains the recommended method for detecting the presence of somatic mutations in human malignancies. V600E is the most frequent somatic point mutation in metastatic melanoma, providing a unique molecular marker for this malignancy. In addition, tumors carrying this mutation are primary candidates for BRAF-targeted therapy.

BIM and mTOR expression levels predict outcome to erlotinib in EGFR-mutant non-small-cell lung cancer.

BIM is a proapoptotic protein that initiates apoptosis triggered by EGFR tyrosine kinase inhibitors (TKI). mTOR negatively regulates apoptosis and may influence response to EGFR TKI. We examined mRNA expression of BIM and MTOR in 57 patients with EGFR-mutant NSCLC from the EURTAC trial.

BRAF mutation analysis in circulating free tumor DNA of melanoma patients treated with BRAF inhibitors.

BRAFV600E is a unique molecular marker for metastatic melanoma, being the most frequent somatic point mutation in this malignancy. Detection of BRAFV600E in blood could have prognostic and predictive value and could be useful for monitoring response to BRAF-targeted therapy. We developed a rapid, sensitive method for the detection and quantification of BRAFV600E in circulating free DNA (cfDNA) isolated from plasma and serum on the basis of a quantitative 5'-nuclease PCR (Taqman) in the presence of a peptide-nucleic acid.

Nondisruptive p53 mutations are associated with shorter survival in patients with advanced non-small cell lung cancer.

Purpose: TP53 mutations in early-stage non-small cell lung cancer (NSCLC) may be associated with worse survival but their prognostic role in advanced NSCLC is controversial. In addition, it remains unclear whether mutated patients represent a clinically homogeneous group.

Experimental Design: We retrospectively examined TP53 mutations and outcome in a training cohort of 318 patients with stage IIIB-IV NSCLC: 125 epidermal growth factor receptor (EGFR) wild-type (wt) and 193 EGFR mutated (mut).

The impact of EGFR T790M mutations and BIM mRNA expression on outcome in patients with EGFR-mutant NSCLC treated with erlotinib or chemotherapy in the randomized phase III EURTAC trial.

Purpose: Concomitant genetic alterations could account for transient clinical responses to tyrosine kinase inhibitors of the EGF receptor (EGFR) in patients harboring activating EGFR mutations.

Experimental Design: We have evaluated the impact of pretreatment somatic EGFR T790M mutations, TP53 mutations, and Bcl-2 interacting mediator of cell death (BCL2L11, also known as BIM) mRNA expression in 95 patients with EGFR-mutant non-small-cell lung cancer (NSCLC) included in the EURTAC trial (trial registration: NCT00446225).

Results: T790M mutations were detected in 65.

EGFR mutation analysis in sputum of lung cancer patients: a multitechnique study.

Objectives: Epidermal growth factor receptor (EGFR) mutations have been identified in lung adenocarcinomas and are associated with high response chance to EGFR tyrosine kinase inhibitors. EGFR mutations can be detected in tumour tissue, cytology specimens and blood from lung cancer patients. Thus far, EGFR mutation analysis has not been systematically demonstrated for sputum samples.

CK-coated magnetic-based beads as a tool to isolate circulating tumor cells (CTCs) in human tumors.

Circulating tumor cells (CTCs) can be detected in the blood of many cancer patients and play a key role in metastasis. In addition, after the development of technologies with the necessary sensitivity and reproducibility, the diagnostic potential of these cells is being actively explored. Recently, the U.

BRCA1, LMO4, and CtIP mRNA expression in erlotinib-treated non-small-cell lung cancer patients with EGFR mutations.

Introduction: Lung adenocarcinoma patients harboring EGFR activating mutations attain improved progression-free survival (PFS) with treatment with epidermal growth factor receptor tyrosine kinase inhibitors. However, patients ultimately relapse, indicating that other genetic factors could influence outcome in such patients. We hypothesized that PFS could be influenced by the expression of genes in DNA repair pathways.

Pharmacogenetics of EGFR in lung cancer: perspectives and clinical applications.

Lung cancer is a lethal disease, and most cases have already disseminated at the time of diagnosis. Driver mutations in the EGFR tyrosine kinase domain (mainly deletions in exon 19 and L858R mutation in exon 21) have been identified in lung adenocarcinomas, mostly in never smokers, at frequencies of 20-60%. The EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib attain a response rate of 70% and progression-free survival of 9-13 months, although there are subgroups of patients with long-lasting remissions.

mRNA expression levels and genetic status of genes involved in the EGFR and NF-κB pathways in metastatic non-small-cell lung cancer patients.

Background: Metastatic non-small-cell lung cancer (NSCLC) has a dismal prognosis. EGFR is overexpressed or mutated in a large proportion of cases. Downstream components of the EGFR pathway and crosstalk with the NF-κB pathway have not been examined at the clinical level.

Pretreatment EGFR T790M mutation and BRCA1 mRNA expression in erlotinib-treated advanced non-small-cell lung cancer patients with EGFR mutations.

Purpose: Advanced non-small-cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations (deletion in exon 19 or L858R) show an impressive progression-free survival of 14 months when treated with erlotinib. However, the presence of EGFR mutations can only imperfectly predict outcome. We hypothesized that progression-free survival could be influenced both by the pretreatment EGFR T790M mutation and by components of DNA repair pathways.

Detection of EGFR mutations with mutation-specific antibodies in stage IV non-small-cell lung cancer.

Background: Immunohistochemistry (IHC) with mutation-specific antibodies may be an ancillary method of detecting EGFR mutations in lung cancer patients.

Methods: EGFR mutation status was analyzed by DNA assays, and compared with IHC results in five non-small-cell lung cancer (NSCLC) cell lines and tumor samples from 78 stage IV NSCLC patients.

Results: IHC correctly identified del 19 in the H1650 and PC9 cell lines, L858R in H1975, and wild-type EGFR in H460 and A549, as well as wild-type EGFR in tumor samples from 22 patients.