Erlotinib Treatment Research Articles

Cross-talk between AMPK and EGFR dependent Signaling in Non-Small Cell Lung Cancer.

Lung cancers globally account for 12% of new cancer cases, 85% of these being Non Small Cell Lung Cancer (NSCLC). Therapies like erlotinib target the key player EGFR, which is mutated in about 10% of lung adenocarcinoma. However, drug insensitivity and resistance caused by second mutations in the EGFR or aberrant bypass signaling have evolved as a major challenge in controlling these tumors. Recently, AMPK activation was proposed to sensitize NSCLC cells against erlotinib treatment. However, the underlying mechanism is largely unknown. In this work we aim to unravel the interplay between 20 proteins that were previously associated with EGFR signaling and erlotinib drug sensitivity. The inferred network shows a high level of agreement with protein-protein interactions reported in STRING and HIPPIE databases. It is further experimentally validated with protein measurements. Moreover, predictions derived from our network model fairly agree with somatic mutations and gene expression data from primary lung adenocarcinoma. Altogether our results support the role of AMPK in EGFR signaling and drug sensitivity.

Effects of epidermal growth factor receptor kinase inhibition on radiation response in canine osteosarcoma cells.

BackgroundRadiation therapy is a palliative treatment modality for canine osteosarcoma, with transient improvement in analgesia observed in many cases. However there is room for improvement in outcome for these patients. It is possible that the addition of sensitizing agents may increase tumor response to radiation therapy and prolong quality of life. Epidermal growth factor receptor (EGFR) expression has been documented in canine osteosarcoma and higher EGFR levels have been correlated to a worse prognosis. However, effects of EGFR inhibition on radiation responsiveness in canine osteosarcoma have not been previously characterized. This study examined the effects of the small molecule EGFR inhibitor erlotinib on canine osteosarcoma radiation responses, target and downstream protein expression in vitro. Additionally, to assess the potential impact of treatment on tumor angiogenesis, vascular endothelial growth factor (VEGF) levels in conditioned media were measured.ResultsErlotinib as a single agent reduced clonogenic survival in two canine osteosarcoma cell lines and enhanced the impact of radiation in one out of three cell lines investigated. In cell viability assays, erlotinib enhanced radiation effects and demonstrated single agent effects. Erlotinib did not alter total levels of EGFR, nor inhibit downstream protein kinase B (PKB/Akt) activation. On the contrary, erlotinib treatment increased phosphorylated Akt in these osteosarcoma cell lines. VEGF levels in conditioned media increased after erlotinib treatment as a single agent and in combination with radiation in two out of three cell lines investigated. However, VEGF levels decreased with erlotinib treatment in the third cell line.ConclusionsErlotinib treatment promoted modest enhancement of radiation effects in canine osteosarcoma cells, and possessed activity as a single agent in some cell lines, indicating a potential role for EGFR inhibition in the treatment of a subset of osteosarcoma patients. The relative radioresistance of osteosarcoma cells does not appear to be related to EGFR signalling exclusively. Angiogenic responses to radiation and kinase inhibitors are similarly likely to be multifactorial and require further investigation.

Integrin α1β1 protects against signs of post-traumatic osteoarthritis in the female murine knee partially via regulation of epidermal growth factor receptor signalling

To investigate the role of integrin α1β1 in the progression of post-traumatic osteoarthritis (PTOA), and elucidate the contribution of epidermal growth factor receptor (EGFR) signalling to the mechanism by which integrin α1β1 might control PTOA. We hypothesised that integrin α1β1 plays a protective role in the course of PTOA and that the effect of PTOA (e.g., synovitis, loss of cartilage and growth of osteophytes) would be exacerbated in mice lacking integrin α1β1 at every time point post destabilisation of medial meniscus (DMM). DMM or sham surgery was performed on integrin α1-null and wild type (WT) mice and the progression of PTOA analysed at 2, 4, 8 and 12 weeks post-surgery (PS) using micro-computed tomography (microCT), histology, and immunohistochemistry. In addition, the effects of EGFR blockade were examined by treating the mice with the EGFR inhibitor erlotinib. Integrin α1-null female, but not male, mice showed earlier cartilage degradation post DMM surgery compared to WT controls. Furthermore, erlotinib treatment resulted in significantly less cartilage damage in integrin α1-null but not WT mice. Independent of genotype, erlotinib treatment significantly mitigated the effects of PTOA on many tissues of female mice including meniscal and fabella bone volume, subchondral bone thickness and density and cartilage degradation. In contrast, reduced EGFR signalling had little effect on signs of PTOA in male mice. Integrin α1β1 protects against PTOA-induced cartilage degradation in female mice partially via the reduction of EGFR signalling. Furthermore, reduction of EGFR signalling protects against the development of PTOA in female, but not male mice.

Genome-wide screen of DNA methylation study in stage IIIa (N2) EGFR 19 deletion adenocarcinoma with erlotinib treatment.

e20067Background: Lung cancer is the leading cause of cancer related death in the world. The challenge of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (...

Synergistic effect of pacritinib with erlotinib on JAK2-mediated resistance in epidermal gowth factor receptor mutation-positive non-small cell lung Cancer

The combination effect of pacritinib, a novel JAK2/FLT3 inhibitor, with erlotinib, the epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), on non-small cell lung cancer cells with EGFR activating mutations was investigated. The combination showed synergistic effects on JAK2-mediated EGFR TKI-resistant PC-9/ER3 cells in some cases. The combination markedly suppressed pAKT and pERK although pSTAT3 expression was similar regardless of treatment with the pacritinib, pacritinib + erlotinib, or control in PC-9/ER3 cells. Receptor tyrosine kinase array profiling demonstrated that pacritinib suppressed MET in the PC-9/ER3 cells. The combined treatment of pacritinib and erlotinib in PC-9/ER3 xenografts showed more tumor shrinkage compared with each drug as monotherapy. Western blotting revealed that pMET in tumor samples was inhibited. These results suggest MET suppression by pacritinib may play a role in overcoming the EGFR-TKI resistance mediated by JAK2 in the PC-9/ER3 cells. In conclusion, pacritinib combined with EGFR-TKI might be a potent strategy against JAK2-mediated EGFR-TKI resistance.

Acute myocardial infarction following erlotinib treatment for NSCLC: A case report.

Erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, is an oral targeted anticancer drug that is used to treat non-small cell lung cancer (NSCLC). Previous studies have confirmed that erlotinib is safe and is well-tolerated by patients. The most common adverse reactions observed following erlotinib treatment include a rash and mild diarrhea. In the current study, the first case of acute myocardial infarction following one month of treatment with erlotinib in a 63-year-old male NSCLC patient is presented. The present study highlights the importance of clinicians remaining cautious following erlotinib administration. In elderly NSCLC patients and those with a history of coronary heart disease, cardiac function must be carefully monitored following erlotinib treatment so that serious adverse reactions, such as myocardial infarction, may be identified early and treated quickly.

Predictive significance of thyroid transcription factor-1 expression in patients with non-squamous non-small cell lung cancer with wild-type epidermal growth factor receptor treated with erlotinib.

Little is known on the efficacy of erlotinib treatment in patients expressing wild-type epidermal growth factor receptor (EGFR). This study is a retrospective review of patients with non-squamous, non-small-cell lung cancer (NS-NSCLC) and wild-type EGFR who were treated with erlotinib alone as second- or later-line chemotherapy at the Tokyo Metropolitan Cancer and Infectious Diseases Center of Komagome Hospital (Tokyo, Japan) between December, 2008 and December, 2013. Thyroid transcription factor-1 (TTF-1) was immunohistochemically analyzed in 26 of 53 patients, among whom 20 (77%) and 6 (23%) were considered as TTF-1-positive and -negative, respectively. The median follow-up of these 26 patients was 133 days (range, 26-873 days). The time-to-treatment failure was significantly longer in TTF-1-positive compared with that in TTF-1-negative patients [49.5 vs. 20.0 days; 95% confidence interval (CI): 28-90 vs. 14-74 days, respectively; P=0.01]. The overall survival was significantly better for TTF-1-positive (227 days; 95% CI: 110-366 days) compared with TTF-1-negative patients (P=0.0002). Therefore, the expression of TTF-1 may serve as a useful tool for predicting the efficacy of erlotinib in patients with NS-NSCLC expressing wild-type EGFR.

WITHDRAWN:Clinical efficacy of erlotinib, a salvage treatment for non-small cell lung cancer patients following gefitinib failure.

Ahead of Print article withdrawn by publisher.

Erlotinib or Chemotherapy in Second-Line or Later Treatment of Tumor EGFR Wild-Type Pulmonary Adenocarcinoma Patients

BackgroundThe intent of this study was to explore the treatment efficacy of erlotinib, pemetrexed or docetaxel in individual patients with tumor EGFR wild-type pulmonary adenocarcinoma who failed previous chemotherapy. MethodsWe retrospectively reviewed the clinical data of our EGFR wild-type pulmonary adenocarcinoma patients who had disease progression after first-line chemotherapy and also had received erlotinib and pemetrexed or docetaxel treatment in our institution any time from July 2009 to June 2012. ResultsForty-one patients were identified and enrolled into the present study; all of them received erlotinib treatment. Thirty-five patients received additional pemetrexed treatment and 30 patients received additional docetaxel treatment, either preceding or following failure of erlotinib treatment. Erlotinib was used more frequently as a second-line treatment in 27 of 41 (65.9%) patients, followed by pemetrexed, which was used more frequently in the third-line setting for 21 of 35 (60%) patients. Docetaxel was typically used as the fourth-line treatment for 14 of 30 (46.7%) patients (all p < 0.01 when comparing different treatment agents). There was no difference in the tumor response rate between erlotinib (19.5%), pemetrexed (17.1%), and docetaxel (6.7%) (p = 0.301). For all patients, the median progression-free survival (PFS) was 10.9 weeks, 13.3 weeks, and 8.3 weeks when using erlotinib, pemetrexed, and docetaxel, respectively, as ≥ second-line treatment (p = 0.0261). No significant difference in PFS was found for individual agents when used in an earlier or later line of salvage therapy. ConclusionsThis retrospective study of tumor EGFR wild-type pulmonary adenocarcinoma patients showed that erlotinib, pemetrexed, or docetaxel, individually, provided effective salvage therapy when patients had disease progression subsequent to first-line chemotherapy.

The Chicago Thoracic Oncology Database Consortium: A Multisite Database Initiative.

Objective: An increasing amount of clinical data is available to biomedical researchers, but specifically designed database and informatics infrastructures are needed to handle this data effectively. Multiple research groups should be able to pool and share this data in an efficient manner. The Chicago Thoracic Oncology Database Consortium (CTODC) was created to standardize data collection and facilitate the pooling and sharing of data at institutions throughout Chicago and across the world. We assessed the CTODC by conducting a proof of principle investigation on lung cancer patients who took erlotinib. This study does not look into epidermal growth factor receptor (EGFR) mutations and tyrosine kinase inhibitors, but rather it discusses the development and utilization of the database involved.Methods: We have implemented the Thoracic Oncology Program Database Project (TOPDP) Microsoft Access, the Thoracic Oncology Research Program (TORP) Velos, and the TORP REDCap databases for translational research efforts. Standard operating procedures (SOPs) were created to document the construction and proper utilization of these databases. These SOPs have been made available freely to other institutions that have implemented their own databases patterned on these SOPs.Results: A cohort of 373 lung cancer patients who took erlotinib was identified. The EGFR mutation statuses of patients were analyzed. Out of the 70 patients that were tested, 55 had mutations while 15 did not. In terms of overall survival and duration of treatment, the cohort demonstrated that EGFR-mutated patients had a longer duration of erlotinib treatment and longer overall survival compared to their EGFR wild-type counterparts who received erlotinib.Discussion: The investigation successfully yielded data from all institutions of the CTODC. While the investigation identified challenges, such as the difficulty of data transfer and potential duplication of patient data, these issues can be resolved with greater cross-communication between institutions of the consortium.Conclusion: The investigation described herein demonstrates the successful data collection from multiple institutions in the context of a collaborative effort. The data presented here can be utilized as the basis for further collaborative efforts and/or development of larger and more streamlined databases within the consortium.

Tumor heterogeneity on 18F-FDG-PET/CT for response monitoring in non-small cell lung cancer treated with erlotinib

Response monitoring using fluorodeoxyglucose positron emission tomography acquired together with low dose computed tomography (FDG-PET/CT) textural features has potential in targeted treatment with erlotinib in non-small cell lung cancer (NSCLC) patients. Patients with substantial decrease of metabolic activity during erlotinib treatment will probably benefit from continued treatment. However, various aspects of the method (quantification tools, cut-off values, etc.) need to be standardized before the software becomes widely available in a similar manner as standardized uptake value (SUV) measurements. Heterogeneity on FDG-PET/CT opened an additional window for innovation but simultaneously a new challenge for molecular hybrid imaging.

Comparison of Skin Toxic Effects Associated With Gefitinib, Erlotinib, or Afatinib Treatment for Non–Small Cell Lung Cancer

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been widely used to treat non–small cell lung cancer. Four major skin toxic effects with different incidences have been reported from clinical studies, including acneiform eruption (60%-94%), pruritus (16%-60%), xerosis (4%-38%), and paronychia (6%-12%). 1,2 However, a direct comparison of the incidences and severities of the 4 types of skin toxic effects for 3 different EGFR-TKIs in the same patient cohort has been lacking to date. Methods | This retrospective study was approved by the research ethics committee of National Taiwan University Hospital. We recruited patients within a named patient program for compassionate use before registration who had ever received afatinib treatment for non–small cell lung cancer between November 1, 2007, and April 30, 2013. Most of the pa

Abstract B03: EGFR and mTORC1 are novel therapeutic targets in nonseminomatous germ cell tumors

Abstract This study aims to identify novel therapeutic targets for nonseminomatous pediatric germ cell tumors (GCTs). GCTs are the most common cancer in young men, and affect both children and adolescents. They are histologically classified into two types: seminomatous GCTs (SGCTs), which are undifferentiated, and non-seminomatous GCTs (NSGCTs), which exhibit differentiation. Although cisplatin treatment is effective for many types of GCTs, cisplatin resistance, which is especially common in NSGCTs, confers poor prognosis for affected patients. However, because the signaling pathways and genes responsible for the development of different types of GCTs are not well-understood, few targeted therapies exist for GCTs, and no specific therapies exist for NSGCTs. Therefore, novel therapies to specifically target NSGCTs are needed. To determine a targetable pathway that is activated in GCTs, we used quantitative RT-PCR to measure the expression of growth factor receptors in pediatric GCTs, immunohistochemistry (IHC) on a panel of clinically annotated germ cell tumors, and Western blot as well as cell viability assays on NSGCT cell lines (NCCIT and NTERA-2) to determine the effect of inhibition of two signaling pathways on cell viability. Our RT-PCR results showed that multiple members of the EGF and FGF receptor families are expressed at higher levels in NSGCTs than SGCTs. In addition, we found that EGF and FGF2 stimulate Ras-MAPK as well as PI3K/mTOR signaling in NSGCT cell lines. Based on IHC staining of phosphorylated ERK1/2, mTOR, and S6 ribosomal protein, we showed that both the Ras-MAPK and PI3K-mTOR pathways are activated at higher levels in NSGCTs than SGCTs. The results suggested that inhibiting EGFR as well as mTORC1 may be effective in impairing the growth and survival of NSGCT cell lines. To test this hypothesis, we examined the effects of two small molecule inhibitors of EGFR and mTOR signaling, erlotinib and rapamycin, respectively, on the survival of NCCIT and NTERA-2 cell lines. We verified by Western blot that erlotinib inhibits components of the Ras-MAPK pathway in NSGCT cell lines, while rapamycin inhibits components of the PI3K-mTOR pathway. Cell survival experiments showed that while treatment with rapamycin or erlotinib alone decreased cell viability, sufficient reduction of survival could only be achieved with high concentrations that are not clinically feasible. However, a combination treatment of erlotinib and rapamycin synergistically inhibited the growth of the two NSGCT cell lines at clinically achievable concentrations. Our findings showed that NSGCTs are dependent on EGFR and mTOR signaling in vitro, and suggest that targeting these signaling pathways may be a promising therapy to specifically target chemoresistant NSGCTs. Citation Format: Albert Budhipramono, Dinesh Rakheja, Kenneth S. Chen, Nicholas Fustino, Abhay Shukla, Jonathan Wickiser, Theodore Laetsch, James F. Amatruda. EGFR and mTORC1 are novel therapeutic targets in nonseminomatous germ cell tumors. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr B03.

Metabolic tumor burden as marker of outcome in advanced EGFR wild-type NSCLC patients treated with erlotinib

ObjectivesAccurate estimation of the prognosis of advanced non-small cell lung cancer (NSCLC) patients is essential before initiation of palliative treatment; especially in the second and third-line setting. This study was conducted in order to evaluate tumor burden measured on an 2′-deoxy-2′-[18F] fluoro-D-glucose (F-18-FDG) positron emission tomography/computed tomography (PET/CT) scan as a marker of outcome in advanced epidermal growth factor receptor (EGFR) wild-type patients treated with second or third-line erlotinib. Material and methodsFifty-one patients were included from a prospectively collected cohort. An F-18-FDG-PET/CT scan was conducted prior to erlotinib treatment and tumor burden was measured in terms of metabolic tumor volume (MTV) and total lesion glycolysis (TLG). Median values of MTV and TLG were used for dichotomization of patients. Survival outcome was compared between groups. ResultsMTV and TLG could be measured in 49 patients. High values of MTV and TLG were significantly correlated with shorter PFS (p<0.001 and p=0.027, respectively) and OS (p<0.001 and p=0.002, respectively). In multivariate analyses, including both clinical and imaging data, high MTV and TLG remained strong independent markers of both shorter PFS (MTV, hazard ratio (HR)=5.44 (95% confidence interval (CI) 2.46–12.02); TLG, HR=2.17 (95% CI 1.11–4.26)) and OS (MTV, HR=4.80 (95% CI 2.08–11.06); TLG, HR=2.76 (95% CI 1.33–5.71)). ConclusionHigh MTV and TLG are independently correlated with shorter PFS and OS in advanced EGFR wild-type NSCLC patients treated with second or third-line erlotinib. Metabolic tumor burden is a highly promising clinical tool that may allow better patient selection for palliative treatment in the future.

Risk of brain metastasis reduced after erlotinib treatment in advanced pulmonary adenocarcinoma patients with sensitive EGFR mutation

PurposeBrain metastasis (BM) is associated with impaired quality of life and increased mortality. The study aimed to compare BM risk after erlotinib administration and chemotherapy in stage IIIB/IV pulmonary adenocarcinoma patients harboring epidermal growth factor receptor (EGFR) mutation.Patients and methodsEligible patients underwent match pair process with matching factors, including age, sex, performance status score, first-line or second-line treatment, first-line chemotherapy regimen (for the second-line treatment subgroup), stage IIIB or IV, and genotypes of EGFR mutation. BM and mortality risk of both groups were recorded and compared.ResultsIn total 129 matched pairs were included for analysis. During a median follow-up of 21.5 months, time to BM risk was longer and incidences of BM within 2 years were lower in patients who received erlotinib than chemotherapy in total population, as well as subgroups of first-line treatment, second-line treatment, stage IIIB, stage IV, exon 19 deletion mutation, and exon 21 L858R mutation. Similar overall survival time and 2-year survival rates were seen in two groups totally or in any subgroup. Multivariate analysis showed that BM was retarded in patients who received erlotinib administration (hazard ratio, 1.695; P=0.001) and in patients who were in stage IIIB (hazard ratio, 1.751; P=0.001).ConclusionErlotinib administration decreases BM risk in advanced pulmonary adenocarcinoma patients harboring sensitive EGFR mutations.

Erlotinib and the Risk of Oral Cancer: The Erlotinib Prevention of Oral Cancer (EPOC) Randomized Clinical Trial.

Standard molecularly based strategies to predict and/or prevent oral cancer development in patients with oral premalignant lesions (OPLs) are lacking. To test if the epidermal growth factor receptor inhibitor erlotinib would reduce oral cancer development in patients with high-risk OPLs defined by specific loss of heterozygosity (LOH) profiles. Secondary objectives included prospective determination of LOH as a prognostic marker in OPLs. The Erlotinib Prevention of Oral Cancer (EPOC) study was a randomized, placebo-controlled, double-bind trial. Accrual occurred from November 2006 through July 2012, with a median follow-up time of 35 months in an ambulatory care setting in 5 US academic referral institutions. Patients with OPLs were enrolled in the protocol, and each underwent LOH profiling (N = 379); they were classified as high-risk (LOH-positive) or low-risk (LOH-negative) patients based on their LOH profiles and oral cancer history. The randomized sample consisted of 150 LOH-positive patients. Oral erlotinib treatment (150 mg/d) or placebo for 12 months. Oral cancer-free survival (CFS). A total of 395 participants were classified with LOH profiles, and 254 were classified LOH positive. Of these, 150 (59%) were randomized, 75 each to the placebo and erlotinib groups. The 3-year CFS rates in placebo- and erlotinib-treated patients were 74% and 70%, respectively (hazard ratio [HR], 1.27; 95% CI, 0.68-2.38; P = .45). The 3-year CFS was significantly lower for LOH-positive compared with LOH-negative groups (74% vs 87%, HR, 2.19; 95% CI, 1.25-3.83; P = .01). Increased EGFR gene copy number correlated with LOH-positive status (P < .001) and lower CFS (P = .01). The EGFR gene copy number was not predictive of erlotinib efficacy. Erlotinib-induced skin rash was associated with improved CFS (P = .01). In this trial, LOH was validated as a marker of oral cancer risk and found to be associated with increased EGFR copy number (the target of the intervention). Erlotinib did not, however, improve CFS in high-risk patients with LOH-positive or high-EGFR-gene-copy-number OPLs. These results support incorporation of LOH testing as a prognostic tool in routine clinical practice but do not support erlotinib use in this setting. clinicaltrials.gov Identifier: NCT00402779.

Serum Metabolite Profiles Are Altered by Erlotinib Treatment and the Integrin α1-Null Genotype but Not by Post-Traumatic Osteoarthritis.

The risk of developing post-traumatic osteoarthritis (PTOA) following joint injury is high. Furthering our understanding of the molecular mechanisms underlying PTOA and/or identifying novel biomarkers for early detection may help to improve treatment outcomes. Increased expression of integrin α1β1 and inhibition of epidermal growth factor receptor (EGFR) signaling protect the knee from spontaneous OA; however, the impact of the integrin α1β1/EGFR axis on PTOA is currently unknown. We sought to determine metabolic changes in serum samples collected from wild-type and integrin α1-null mice that underwent surgery to destabilize the medial meniscus and were treated with the EGFR inhibitor erlotinib. Following (1)H nuclear magnetic resonance spectroscopy, we generated multivariate statistical models that distinguished between the metabolic profiles of erlotinib- versus vehicle-treated mice and the integrin α1-null versus wild-type mouse genotype. Our results show the sex-dependent effects of erlotinib treatment and highlight glutamine as a metabolite that counteracts this treatment. Furthermore, we identified a set of metabolites associated with increased reactive oxygen species production, susceptibility to OA, and regulation of TRP channels in α1-null mice. Our study indicates that systemic pharmacological and genetic factors have a greater effect on serum metabolic profiles than site-specific factors such as surgery.

Preclinical Study of a Combination of Erlotinib and Bevacizumab in Early Stages of Unselected Non-Small Cell Lung Cancer Patient-Derived Xenografts.

The differential outcomes of clinical studies of the targeted therapies for non-small cell lung cancer (NSCLC) indicate that better stratification of patients is required. This could be achieved with the help of patient-derived xenografts (PDX) of epidermal growth factor receptor (EGFR) wild-type patients resistant to erlotinib treatment. To explore the potential of patient-derived NSCLC xenografts to optimize therapy using 24 well-characterized early-stage NSCLC PDX. Patient tumor tissue was transplanted subcutaneously into nude mice. After engraftment, tumors were expanded and the sensitivity was tested. Gene expression analysis was used to identify differentially expressed genes between erlotinib responder (n = 3) and non-responder (n = 21). Tumor tissue was analyzed with TaqMan PCR, immunohistochemistry and ELISA to examine the response of the models. Gene expression analysis revealed vascular endothelial growth factor A (VEGFA) to be up-regulated in erlotinib non-responder. Because of that, the combination of erlotinib with bevacizumab was evaluated in one erlotinib-sensitive and four erlotinib-resistant PDX. Combination treatment was superior to monotherapy, leading to the highest and significant inhibition of tumor growth in all models investigated. A decline of VEGFA protein and an increase of VEGFA-mRNA were observed after bevacizumab treatment. Bevacizumab treatment resulted in a distinct decrease of blood vessel number. This study showed that with the help of preclinical PDX models, drug combinations for therapy improvement can be identified on a rational basis. It was observed that a dual blockage of EGFR and VEGFA was more effective than a monotherapy for the treatment of NSCLC in selected PDX models. PDX could be employed to optimize the treatment of cancer patients.

Dosing to rash? – The role of erlotinib metabolic ratio from patient serum in the search of predictive biomarkers for EGFR inhibitor-mediated skin rash

AimThe aim of this study was to investigate if biomarkers of individual drug metabolism, respectively, the erlotinib/O-desmethyl-erlotinib metabolic ratio, may be a predictive factor for the severity of erlotinib-mediated skin rash in epidermal growth factor receptor (EGFR) inhibitor-treated patients suffering from epithelial cancers. This is especially important since it is known that the severity of skin rash has a prognostic value on outcome and survival in cancer patients experiencing skin rash under treatment with EGFR inhibitors. MethodsFrom 2008 to 2014, 96 patients, n = 63 suffering from histologically confirmed non-small-cell lung cancer and n = 33 from pancreatic adenocarcinoma were observed for the occurrence and severity of skin rash after the onset of treatment with erlotinib. The primary end-points (occurrence and severity of skin rash, progression-free survival [PFS] and overall survival [OS]) were analysed with regard to erlotinib and its metabolite O-desmethyl-erlotinib trough serum concentrations measured at 4 weeks after onset of therapy by the use of correlation, multiple regression and survival analysis. ResultsOccurrence of skin rash was associated with PFS (p = 0.0042) and OS (p = 0.017) in the overall cohort of erlotinib-treated cancer patients. Drug-metabolising activity assessed by the erlotinib/O-desmethyl-erlotinib metabolic ratio was correlated with severity of skin rash (p = 0.023) and as well highly associated with both PFS (p = 2.1 × 10−4) and OS (p = 5.8 × 10−5). ConclusionThe erlotinib/O-desmethyl-erlotinib metabolic ratio reflecting the individual metabolic activity of erlotinib correlated with the severity of skin rash and outcome in patients treated with EGFR tyrosine kinase inhibitors. The metabolic ratio determined in serum may be used for therapeutic monitoring in erlotinib treatment and decisions on individual dosing to rash in rash-negative patients.

Targeting non-canonical autophagy overcomes erlotinib resistance in tongue cancer.

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) frequently occurs in many human cancers and hampers their therapeutic use. A large body of evidence has demonstrated the pro-survival role of autophagy in many human cancers. However, whether autophagy is involved in the induction of erlotinib resistance in tongue squamous cell carcinoma (TSCC) remains unknown. In this report, we found that autophagy prior to or induced by erlotinib treatment plays an important role in erlotinib resistance in tongue cancer cells. Using LC3 transfection, we observed that autophagy is upregulated and further induced when treated with erlotinib. Moreover, we found that autophagy plays a cytoprotective role by MTT analysis of the cell viability in TSCCs when treated with rapamycin or hydroxychloroquine (HCQ) in combination with erlotinib. However, 3-methyladenine (3-MA) did not influence the autophagy. Then, through siRNA technology and WB, we found that erlotinib-induced autophagy is mediated by ATG5 but not Beclin1. Also, knockdown of ATG5 significantly decreased the erlotinib resistance and knockdown of Beclin1 did not affect the sensitivity to erlotinib in TSCCs. Taken together, this indicates the critical role of non-canonical autophagy in erlotinib resistance in TSCCs.