0000000000041036
AUTHOR
Ines Pulido
Intratumoral Heterogeneity in EGFR-Mutant NSCLC Results in Divergent Resistance Mechanisms in Response to EGFR Tyrosine Kinase Inhibition
Abstract Non–small cell lung cancers (NSCLC) that have developed resistance to EGF receptor (EGFR) tyrosine kinase inhibitor (TKI), including gefitinib and erlotinib, are clinically linked to an epithelial-to-mesenchymal transition (EMT) phenotype. Here, we examined whether modulating EMT maintains the responsiveness of EGFR-mutated NSCLCs to EGFR TKI therapy. Using human NSCLC cell lines harboring mutated EGFR and a transgenic mouse model of lung cancer driven by mutant EGFR (EGFR-Del19-T790M), we demonstrate that EGFR inhibition induces TGFβ secretion followed by SMAD pathway activation, an event that promotes EMT. Chronic exposure of EGFR-mutated NSCLC cells to TGFβ was sufficient to ind…
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…
Pterostilbene Prevents Early Diabetic Retinopathy Alterations in a Rabbit Experimental Model
Oxidative stress generated by diabetes plays a key role in the development of diabetic retinopathy (DR), a common diabetic complication. DR remains asymptomatic until it reaches advanced stages, which complicate its treatment. Although it is known that good metabolic control is essential for preventing DR, knowledge of the disease is incomplete and an effective treatment with no side effects is lacking. Pterostilbene (Pter), a natural stilbene with good antioxidant activity, has proved to beneficially affect different pathologies, including diabetes. Therefore, our study aimed to analyse the protective and/or therapeutic capacity of Pter against oxidant damage by characterising early retina…
Abstract C75: Overcoming KRAS/LKB1 mutant NSCLC resistance to BET bromodomain inhibitors with gemcitabine or Mcl-1 inhibition
Abstract The purpose of our study was to define a method and mechanism for overcoming the resistance of clinically relevant KRAS-mutant/LKB1-deficient NSCLC cells to the BET-bromodomain inhibitor JQ1. LKB1 (Serine/threonine kinase 11) is mutated with loss of function in conjunction with mutated KRAS in 7-10% of NSCLC. Importantly, KRAS-mutant/LKB1-deficiency is associated with tumor aggressiveness and poor survival in human patients as well as in genetically engineered mouse models. Indeed, although the BET bromodomain inhibitor JQ1 dramatically reduces tumor volume in KRAS mutant mice, it has little effect in KRAS-mutant/LKB1-deficient mice. BET bromodomain proteins are chromatin readers t…
Abstract A292: Salinomycin, an anti-cancer stem cell antibiotic, overcomes acquired resistance to BRAF inhibitors in BRAF-mutant human melanoma cell lines.
Abstract Advanced malignant melanoma is one of the most lethal cancers, because it is highly metastatic and refractory to conventional chemotherapy. About 60% of melanomas harbor oncogenic BRAF mutations which aberrantly activate MEK/ERK signaling pathway. BRAF and MEK inhibitors have been shown efficacious in patients with BRAF-mutant melanoma, but there is not effective target therapy for BRAF wild type melanomas. Unfortunately acquired resistance to BRAF targeted therapies is a common event: 50% of treated patients progressed within 6 to 7 months after the initiation of treatment. Resistance is associated with reactivation of the MAPK pathway (through development of de novo NRAS, NF1 or …
Abstract LB-085: A new role for LKB1 to regulate Heat Shock Protein 90 activity
Abstract Approximately 30% of human non-small cell lung cancer (NSCLC) patients harbor a somatic KRAS mutation resulting, in aberrant activation of downstream signaling pathways that control cell proliferation, cell growth, and cell survival. Importantly, alleles of LKB1, a serine/threonine kinase that functions as a tumor suppressor, are somatically inactivated in ~30% of NSCLCs within KRAS-mutant NSCLC. The loss of LKB1 gives rise to aggressive, highly metastatic, and highly drug resistant tumors. We have previously demonstrated that the inactivation of the tumor suppressor lkb1 rendered mutant kras murine NSCLC resistant to targeted agents including BET bromodomain and kinase inhibitors.…
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…
Abstract 753: Genomic alterations of autophagy genes disrupts autophagic flux in human lung adenocarcinomas
Abstract Targeted therapy using EGFR tyrosine kinase inhibitor (TKI) is a standard therapy for a subset of non-small cell lung cancer (NSCLC) patients with lung adenocarcinomas (LADs) harboring EGFR kinase domain mutations; however, EGFR TKI therapy shows limited efficacy due to de novo and acquired resistance. Consequently, formulating strategies to potentiate the efficacy of EGFR TKI is of great interest. In EGFR TKI sensitive cells harboring EGFR mutation, it has been shown that EGFR inhibition induces autophagy to protect the cells from metabolic stress. Hydroxychloroquine (HQ), an inhibitor of autophagy, has been shown to potentiate EGFR TKIs in preclinical models, however, preliminary…
Abstract 20: Inhibition of mutant EGFR in NSCLC promotes endothelin-1-mediated NSCLC disease progression and angiogenesis
Abstract Despite recent advances in the treatment of NSCLC targeting of EGFR kinase domain mutations with tyrosine kinase inhibitors (TKIs), work needs to be done to reduce morbidity and improve survival for NSCLC patients. In NSCLC, tumor angiogenesis has been identified as important therapeutic target in combination with EGFR TKIs. However, only small advancements have been made for the use of angiogenesis inhibitors in NSCLC and it remains elusive why the inhibition of VEGF-mediated neovascularization is not therapeutically efficacious. We present evidence that a subpopulation of NSCLC cells with the EGFR TKI-induced epithelial to mesenchymal transition (EMT) contributes to the attenuati…
Endothelin-1-Mediated Drug Resistance in EGFR-Mutant Non-Small Cell Lung Carcinoma.
Abstract Progression on therapy in non-small cell lung carcinoma (NSCLC) is often evaluated radiographically, however, image-based evaluation of said therapies may not distinguish disease progression due to intrinsic tumor drug resistance or inefficient tumor penetration of the drugs. Here we report that the inhibition of mutated EGFR promotes the secretion of a potent vasoconstrictor, endothelin-1 (EDN1), which continues to increase as the cells become resistant with a mesenchymal phenotype. As EDN1 and its receptor (EDNR) is linked to cancer progression, EDNR-antagonists have been evaluated in several clinical trials with disappointing results. These trials were based on a hypothesis that…
Abstract LB-C21: CXCR7 expression is necessary for the maintenance of mesenchymal phenotype in acquired EGFR TKI resistance in NSCLC
Abstract Activating EGFR mutations in non-small lung cancer (NSCLC) confer sensitivity to reversible EGFR tyrosine kinase inhibitors (TKIs), including gefitinib and erlotinib. Despite promising initial response, acquired resistance develops mediated by the emergence of the secondary T790M mutation or by focal amplification of MET. An epithelial-to-mesenchymal transition (EMT) is clinically linked to NSCLCs with acquired EGFR TKI resistance. The exact mechanisms of EGFR TKI resistance with EMT phenotype remain elusive; therefore, we have engineered EGFR-mutated NSCLC cell lines with mesenchymal phenotype by stably depleting E-Cadherin or by overexpressing Snail or chronically exposing the ce…
Abstract 1605: Pterostilbene, a natural phytoalexin, effectively protects against UVB-induced skin carcinogenesis by increasing antioxidant cellular defenses and preventing mutagenesis
Abstract Clinical and laboratory studies have demonstrated that skin exposure to ultraviolet radiation (UV) is the main cause of non-melanoma skin cancer (NMSC) (≈ 99%) and melanoma (≈ 95%) development. The procarcinogenic effects of solar exposure are mainly due to UVB radiation (290-320 nm range), the same tight range that produces burning in human skin (erythema), inflammation, oxidative stress, DNA damage, etc. The number of skin cancers around the world keeps increasing and, thus, it is an urgent need to find effective protection remedies. Phytoalexins of polyphenolic structure are naturally occurring compounds involved in the defense against pathogens and environmental stresses in pla…
Abstract 1280: Pterostilbene exerts full protection against UVB-induced skin carcinogenesis.
Abstract Epidemiological, clinical and laboratory studies have demonstrated that solar ultraviolet (UV) radiation is the main cause of nonmelanoma skin cancer (i.e., basal cell and squamous cell carcinoma) and it is also a prime factor in the etiology of cutaneous melanoma. The cancer-causing effects of solar exposure on the skin are mainly produced by UV-B radiation in the 290- to 320-nm range, the same range that produces burning in human skin (erythema), inflammation, oxidative stress, DNA damage, etc. Thus, and considering the alarming numbers of skin cancers being diagnosed around the world, it is increasingly evident the need of an effective protection against UV radiation. Polyphenol…
Abstract 766: Suppression of gefitinib-induced EMT in EGFR mutant NSCLC preferentially selects for acquired T790M
Abstract Activating EGFR mutations in non-small lung cancer (NSCLC) confer sensitivity to reversible EGFR tyrosine kinase inhibitors (TKIs), including gefitinib and erlotinib. Despite promising initial response acquired resistance develops mediated by the emergence of the secondary T790M mutation or by focal amplification of MET. An epithelial-to-mesenchymal transition (EMT) is clinically linked to NSCLCs with acquired EGFR TKI resistance. The exact mechanisms of EGFR TKI resistance with EMT phenotype remain elusive; therefore, we attempted to develop a strategy to prevent the emergence of EGFR TKI resistance with EMT phenotype. In order to mimic the development of acquired EGFR TKI resista…
Abstract 1690: Differential autophagy activation in KRAS and EGFR mutant lung adenocarcinomas.
Abstract Lung cancer is the leading cause of cancer deaths in western countries, and adenocarcinomas (LADs) are the most frequent histological subtype. The aberrant activation of the kinases promotes plethora of tumorigenic processes, mainly through PI3K and MAPK oncogenic pathways leading to oncogene addiction. The activation of PI3K pathway deregulates mTOR, a master kinase for cell growth and autophagy. Autophagy can be pro- or anti- tumorigenic, however its roles in protecting tumors exposed to metabolic stress under chemotherapy are considered as a survival mechanism for the tumors leading to acquired resistance. Consequently, the inhibition of autophagy is an attractive therapy to pre…