High spatiotemporal heterogeneity, clonal selection and neoantigen evolution in acquired sorafenib-resistant patient-derived xenograft models of hepatocellular carcinoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15641-e15641
Author(s):  
Xin-Rong Yang ◽  
Bo Hu ◽  
Jian Zhou ◽  
Jia Fan
Keyword(s):  
Drug Resistance ◽  
Clonal Selection ◽  
Acquired Resistance ◽  
Tumor Mutation Burden ◽  
Acquired Drug Resistance ◽  
Patient Derived Xenograft ◽  
Mutation Burden ◽  
Spatiotemporal Heterogeneity ◽  
Pdx Models ◽  
Syngeneic Tumors

e15641 Background: Patient-derived xenograft (PDX) models have been regarded as valuable preclinical models for oncology drug development and exploring underlying mechanism of drug resistance. As the standard treatment option for advanced hepatocellular carcinoma (HCC), the survival benefit of sorafenib is modest. Even among those who initially responded well to sorafenib treatment, most patients ultimately develop progressive disease owing to acquired drug resistance. Understanding how selective pressure from sorafenib directs the evolution of HCC and shapes its clonal architecture is a central biological question with important clinical implications to combat acquired drug resistance. Methods: Three sorafenib-resistant PDX models were generated by continuous sorafenib treament for more than six months. Whole exome sequencing (WES) and RNA sequencing were performed. The subclone of mutation, fusion genes, and the evolving landscape of tumor neoantigens were further explored. Finally, the antitumor efficacy of recombinant mouse PD-1 antibody was evaluated in sorafenib resistance syngeneic tumors model by immune-competent C57BL/6J mice with Hepa 1-6. Results: High spatiotemporal heterogeneity was observed in engraftment among pre- and post- sorafenib resistance in established acquired-resistance PDX models. Clonal selection on engraftment was observed in established acquired-resistance PDX models. There are many high expressed genes, which showed subclone expansion with the emergence of sorafenib resistance. There is vary difference of neoantigens between pre- and post-resistance engraftment as well as sampling points in same tissues. It was presented that a high burden of clonal neoantigens in sorafenib resistant tissues (P < 0.05), while there has no difference in tumor mutation burden. Moreover, the intra-tumor heterogeneity upon the neoantigen landscape was much bigger than that upon tumor mutation burden. We found that fusion subclone sizes were increased significantly after sorafenib resistance (P < 0.05). Finally, the antitumor efficacy of recombinant mouse PD-1 antibody was confirmed in sorafenib resistance syngeneic tumors mice model (P < 0.001). Conclusions: High spatiotemporal heterogeneity, clonal selection and neoantigen evolution was observed in acquired sorafenib-resistant PDX model of HCC. Immunotherapy such as immune checkpoint inhibitors might be a promising strategy for HCC patients with acquired sorafenib resistance. .

scholarly journals A histone methyltransferase inhibitor can reverse epigenetically acquired drug resistance in the malaria parasite Plasmodium falciparum

2019 ◽  
Author(s):  
Amanda Chan ◽  
Alexis Dziedziech ◽  
Laura A Kirkman ◽  
Kirk W Deitsch ◽  
Johan Ankarklev
Keyword(s):  
Gene Expression ◽  
Drug Resistance ◽  
Acquired Resistance ◽  
Anion Channel ◽  
Histone Methyltransferase ◽  
Drug Uptake ◽  
Natural Setting ◽  
Membrane Expression ◽  
Acquired Drug Resistance ◽  
Histone Modifiers

AbstractMalaria parasites invade and replicate within red blood cells (RBCs), extensively modifying their structure and gaining access to the extracellular environment by placing the plasmodial surface anion channel (PSAC) into the RBC membrane. Expression of members of the cytoadherence linked antigen gene 3 (clag3) family is required for PSAC activity, a process that is regulated epigenetically. PSAC is a well-established route of uptake for large, hydrophilic antimalarial compounds and parasites can acquire resistance by silencing clag3 gene expression, thereby reducing drug uptake. We found that exposure to sub-IC50 concentrations of the histone methyltransferase inhibitor chaetocin caused substantial changes in both clag3 gene expression and RBC permeability, reversing acquired resistance to the antimalarial compound blasticidin S that is transported through PSAC. Chaetocin treatment also altered progression of parasites through their replicative cycle, presumably by changing their ability to modify chromatin appropriately to enable DNA replication. These results indicate that targeting histone modifiers could represent a novel tool for reversing epigenetically acquired drug resistance in P. falciparum.ImportanceDrug resistance is a major concern for the treatment of infectious diseases throughout the world. For malaria, a novel mechanism of resistance was recently described in which epigenetic modifications led to a resistance phenotype that is rapidly reversible, thus reducing the fitness cost that is often associated with genetic mutations that lead to resistance. The possibility of this type of resistance arising in a natural setting is particularly troubling since parasites could rapidly switch to and from a resistant phenotype, thus making it especially difficult to combat. Here we show that application of a histone methyltransferase inhibitor can rapidly reverse the epigenetic changes that lead to drug resistance, thereby causing parasites to revert to a drug sensitive phenotype. This is a novel application of drugs that target epigenetic modifiers and lends additional support for ongoing efforts to develop drugs against malaria that target the histone modifiers of the parasite.

scholarly journals A Simple Three-Dimensional In Vitro Culture Mimicking the In Vivo-Like Cell Behavior of Bladder Patient-Derived Xenograft Models

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1304
Author(s):  
Robson Amaral ◽  
Maike Zimmermann ◽  
Ai-Hong Ma ◽  
Hongyong Zhang ◽  
Kamilla Swiech ◽  
...  
Keyword(s):  
Drug Resistance ◽  
In Vitro Culture ◽  
Cancer Cells ◽  
Low Cost ◽  
Maintenance Cost ◽  
Tumor Spheroids ◽  
Patient Derived Xenograft ◽  
Pdx Models

Patient-derived xenograft (PDX) models allow for personalized drug selection and the identification of drug resistance mechanisms in cancer cells. However, PDX models present technical disadvantages, such as long engraftment time, low success rate, and high maintenance cost. On the other hand, tumor spheroids are emerging as an in vitro alternative model that can maintain the phenotype of cancer cells long enough to perform all assays and predict a patient’s outcome. The present work aimed to describe a simple, reproducible, and low-cost 3D in vitro culture method to generate bladder tumor spheroids using human cells from PDX mice. Cancer cells from PDX BL0293 and BL0808 models, previously established from advanced bladder cancer, were cultured in 96-well round-bottom ultra-low attachment (ULA) plates with 5% Matrigel and generated regular and round-shaped spheroids (roundness > 0.8) with a diameter larger than 400 μm and a hypoxic core (a feature related to drug resistance in solid tumors). The responses of the tumor spheroids to the antineoplastic drugs cisplatin, gemcitabine, and their combination were similar to tumor responses in in vivo studies with PDX BL0293 and BL0808 mice. Therefore, the in vitro 3D model using PDX tumor spheroids appears as a valuable tool that may predict the outcome of in vivo drug-screening assays and represents a low-cost strategy for such purpose.

Abstract 752: Rapid acquired resistance to alectinib in ALK-positive lung cancers with high tumor mutation burden

2019 ◽  
Author(s):  
Kadoaki Ohashi ◽  
Go Makimoto ◽  
Shuta Tomida ◽  
Kazuya Nishii ◽  
Shinichi Toyooka ◽  
...  
Keyword(s):  
Acquired Resistance ◽  
Tumor Mutation Burden ◽  
Lung Cancers ◽  
Mutation Burden ◽  
Alk Positive

scholarly journals Acquired Resistance to Clinical Cancer Therapy: A Twist in Physiological Signaling

2016 ◽  
Vol 96 (3) ◽  
pp. 805-829 ◽  
Author(s):  
Andreas Wicki ◽  
Mario Mandalà ◽  
Daniela Massi ◽  
Daniela Taverna ◽  
Huifang Tang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Immune System ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Acquired Resistance ◽  
Therapeutic Strategies ◽  
Host Immune System ◽  
Cancer Therapies ◽  
Acquired Drug Resistance ◽  
Physiological Signal

Although modern therapeutic strategies have brought significant progress to cancer care in the last 30 years, drug resistance to targeted monotherapies has emerged as a major challenge. Aberrant regulation of multiple physiological signaling pathways indispensable for developmental and metabolic homeostasis, such as hyperactivation of pro-survival signaling axes, loss of suppressive regulations, and impaired functionalities of the immune system, have been extensively investigated aiming to understand the diversity of molecular mechanisms that underlie cancer development and progression. In this review, we intend to discuss the molecular mechanisms of how conventional physiological signal transduction confers to acquired drug resistance in cancer patients. We will particularly focus on protooncogenic receptor kinase inhibition-elicited tumor cell adaptation through two major core downstream signaling cascades, the PI3K/Akt and MAPK pathways. These pathways are crucial for cell growth and differentiation and are frequently hyperactivated during tumorigenesis. In addition, we also emphasize the emerging roles of the deregulated host immune system that may actively promote cancer progression and attenuate immunosurveillance in cancer therapies. Understanding these mechanisms may help to develop more effective therapeutic strategies that are able to keep the tumor in check and even possibly turn cancer into a chronic disease.

scholarly journals APOBEC3A drives acquired resistance to targeted therapies in non-small cell lung cancer

2021 ◽  
Author(s):  
Hideko Isozaki ◽  
Ammal Abbasi ◽  
Naveed Nikpour ◽  
Adam Langenbucher ◽  
Wenjia Su ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Targeted Therapy ◽  
Small Cell Lung Cancer ◽  
Targeted Therapies ◽  
Acquired Resistance ◽  
Small Cell ◽  
Tumor Evolution ◽  
Small Cell Lung ◽  
Acquired Drug Resistance

AbstractAcquired drug resistance to even the most effective anti-cancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified1‒6, the underlying molecular mechanisms shaping tumor evolution during treatment are incompletely understood. The extent to which therapy actively drives tumor evolution by promoting mutagenic processes7 or simply provides the selective pressure necessary for the outgrowth of drug-resistant clones8 remains an open question. Here, we report that lung cancer targeted therapies commonly used in the clinic induce the expression of cytidine deaminase APOBEC3A (A3A), leading to sustained mutagenesis in drug-tolerant cancer cells persisting during therapy. Induction of A3A facilitated the formation of double-strand DNA breaks (DSBs) in cycling drug-treated cells, and fully resistant clones that evolved from drug-tolerant intermediates exhibited an elevated burden of chromosomal aberrations such as copy number alterations and structural variations. Preventing therapy-induced A3A mutagenesis either by gene deletion or RNAi-mediated suppression delayed the emergence of drug resistance. Finally, we observed accumulation of A3A mutations in lung cancer patients who developed drug resistance after treatment with sequential targeted therapies. These data suggest that induction of A3A mutagenesis in response to targeted therapy treatment may facilitate the development of acquired resistance in non-small-cell lung cancer. Thus, suppressing expression or enzymatic activity of A3A may represent a potential therapeutic strategy to prevent or delay acquired resistance to lung cancer targeted therapy.

scholarly journals Integrative Genomic Analysis of Drug Resistance in MET Exon 14 Skipping Lung Cancer Using Patient-Derived Xenograft Models

2022 ◽  
Author(s):  
Yunhua Xu ◽  
Linping Gu ◽  
Yingqi Li ◽  
Ruiying Zhao ◽  
Hong Jian ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Targeted Therapy ◽  
Rna Sequencing ◽  
Nsclc Patient ◽  
Genomic Analysis ◽  
Sequencing Analysis ◽  
Patient Derived Xenograft ◽  
Pdx Models

Abstract Background Non-small cell lung cancer (NSCLC) driven by MET exon 14 skipping (METex14) occurs in 3-4% of NSCLC cases and defines a subset of patients with distinct characteristics. MET targeted therapy has led to strong clinical responses, however little is known about aquired resistance to drugs in these patients. Patient derived xenograft (PDX) models are recognized as excellent preclinical models to facilitate the understanding of the mechanisms underlying drug resistance. Methods We describe a patient case harboring METex14 who exhibited drug resistance after treatment with crizotinib. Subcutaneous xenografts were generated from pretreatment and post-resistance patient specimens. PDX mice were then treated with MET inhibitors (crizotinib and tepotinib) to evaluate their drug response. DNA and RNA sequencing analysis was performed on patient tumor specimens and matching xenografts. Results PDXs preserved most of the histological and molecular profiles of the parental tumors. Drug resistance to MET targeted therapy was confirmed in PDX models through in vivo drug analysis. Newly aquired MET D1228N mutations and EGFR amplificated were detected in patient-resistant tumor specimens. Although the mutations were not detected in the PDX, EGFR overexpression was observed in RNA sequencing analysis indicating possible off target resistance through the EGFR bypass signaling pathway. Conclusions We established and characterized a pair of METex14 NSCLC patient-derived xenografts (PDXs), including the first crizotinib resistant METex14 PDX. This model will be a powerful tool for testing hypotheses of drug resistance mechanisms and investigations into novel therapeutic strategies.

Abstract 752: Rapid acquired resistance to alectinib in ALK-positive lung cancers with high tumor mutation burden

2019 ◽  
Author(s):  
Kadoaki Ohashi ◽  
Go Makimoto ◽  
Shuta Tomida ◽  
Kazuya Nishii ◽  
Shinichi Toyooka ◽  
...  
Keyword(s):  
Acquired Resistance ◽  
Tumor Mutation Burden ◽  
Lung Cancers ◽  
Mutation Burden ◽  
Alk Positive

Genomic profiling of squamous malignancies across anatomic sites.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11512-11512 ◽  
Author(s):  
Christine H. Chung ◽  
Garrett Michael Frampton ◽  
Zachary Rockow Chalmers ◽  
Jon Chung ◽  
Saad A. Khan ◽  
...  
Keyword(s):  
Clinical Care ◽  
Acquired Resistance ◽  
Therapy Response ◽  
Subsequent Development ◽  
Genomic Profiling ◽  
Tumor Mutation Burden ◽  
Genomic Features ◽  
Mutation Burden ◽  
Hpv Status ◽  
Allelic Deletion

11512 Background: Primary squamous cell carcinomas (SCCs) have diverse etiologies, but can share genomic features. We reviewed the genomic profiles of a series of SCC cases of differing anatomic origin. Methods: Hybrid-capture based genomic profiling of 182 or 236 or 315 genes was performed on 4783 squamous malignancies in the course of clinical care, with baits for HPV6, 11, 16, and 18, and assessment of tumor mutation burden (TMB; mutations/Mb) and microsatellite instability. Results: Sites of origin were head and neck (HNSCC, n = 1300), cervical (cSCC; n = 318), anal (aSCC, n = 248), esophageal (n = 242), lung (lSCC, n = 2386), and cutaneous (sSCC, n = 289) SCC cases. For HNSCC, cSCC, and aSCC (collectively termed HCA SCC), 395 (30%), 215 (68%), and 211 (83%) were HPV positive, respectively. For HCA SCC, the most common GA were in TP53 (45%), CDKN2A (29%), PIK3CA (24%), TERT (21%), and FAT1 (14%). The most frequent GA differentially associated with HPV status were in PIK3CA (34.9% versus 16.0%), CYLD (11.4% versus 1.4%) and PTEN (14.8% versus 6.1%) for HPV+ cases, and TP53 (3.8% versus 76.5%), CDKN2A ()1.4% versus 49.8%), and TERT (4.3% versus 33.0%) for HPV- cases. Mean TMB for HPV+ and HPV- cases were 6.6 (STDEV 7.3) and 13.7 (STDEV 29.7), respectively. TMB of all SCC cases was significantly different (p < 10-12) when stratified by HPV status. For lSCC and eSCC, the most common GA were found in TP53 (86%) CDKN2A (40%), and PIK3CA (26%) and mean TMB was 11.6 with HPV found in 3.1% of cases. In sSCC, the most common GA were in TP53 (85.5%), CDKN2A (54.3%), and TERT(44.0%), and mean TMB was 59.5 with HPV in 3.1% of cases. Subsets of SCC cases had defining and targetable GA including bi-allelic deletion of SMARCB1 ( < 0.3%), amplification of PD-L1 (~2% ), and various kinase fusions. Cases demonstrating radiologic response to immunotherapy and matched targeted therapies, as well as subsequent development of multiple mechanisms of acquired resistance, will be presented. Conclusions: HPV driven SCC have similar genomic profiles regardless of of site origin, and have a significantly lower median TMB than HPV negative SCC. Early consistency of responses of SCC to matched therapies may strengthen the case for site independent genomic predictors of therapy response.

scholarly journals Nrf2 overexpression increases risk of high tumor mutation burden in acute myeloid leukemia by inhibiting MSH2

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ping Liu ◽  
Dan Ma ◽  
Ping Wang ◽  
Chengyun Pan ◽  
Qin Fang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Acute Myeloid Leukemia ◽  
Gene Mutation ◽  
Myeloid Leukemia ◽  
Related Factor ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Msh2 Protein ◽  
Nrf2 Expression ◽  
Acute Myeloid

AbstractNuclear factor erythroid 2-related factor 2 (Nrf2, also called NFE2L2) plays an important role in cancer chemoresistance. However, little is known about the role of Nrf2 in tumor mutation burden and the effect of Nrf2 in modulating DNA mismatch repair (MMR) gene in acute myeloid leukemia (AML). Here we show that Nrf2 expression is associated with tumor mutation burden in AML. Patients with Nrf2 overexpression had a higher frequency of gene mutation and drug resistance. Nrf2 overexpression protected the AML cells from apoptosis induced by cytarabine in vitro and increased the risk of drug resistance associated with a gene mutation in vivo. Furthermore, Nrf2 overexpression inhibited MutS Homolog 2 (MSH2) protein expression, which caused DNA MMR deficiency. Mechanistically, the inhibition of MSH2 by Nrf2 was in a ROS-independent manner. Further studies showed that an increased activation of JNK/c-Jun signaling in Nrf2 overexpression cells inhibited the expression of the MSH2 protein. Our findings provide evidence that high Nrf2 expression can induce gene instability-dependent drug resistance in AML. This study demonstrates the reason why the high Nrf2 expression leads to the increase of gene mutation frequency in AML, and provides a new strategy for clinical practice.

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