Chemosensitive Relapse in Small Cell Lung Cancer Proceeds through an EZH2-SLFN11 Axis
TL;DR: Inclusion of an EZH2 inhibitor with standard cytotoxic therapies prevented emergence of acquired resistance and augmented chemotherapeutic efficacy in both chemosensitive and chemoresistant models of small cell lung cancer.
About: This article is published in Cancer Cell.The article was published on 2017-02-13 and is currently open access. It has received 341 citations till now. The article focuses on the topics: Etoposide.
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TL;DR: Over the past 5 years, there has been a worldwide resurgence of studies on SCLC, including comprehensive molecular analyses, the development of relevant genetically engineered mouse models and the establishment of patient-derived xenografts, which have led to the discovery of new potential therapeutic vulnerabilities for SCLc and therefore to new clinical trials.
Abstract: Small-cell lung cancer (SCLC) is a deadly tumour accounting for approximately 15% of lung cancers and is pathologically, molecularly, biologically and clinically very different from other lung cancers. While the majority of tumours express a neuroendocrine programme (integrating neural and endocrine properties), an important subset of tumours have low or absent expression of this programme. The probable initiating molecular events are inactivation of TP53 and RB1, as well as frequent disruption of several signalling networks, including Notch signalling. SCLC, when diagnosed, is usually widely metastatic and initially responds to cytotoxic therapy but nearly always rapidly relapses with resistance to further therapies. There were no important therapeutic clinical advances for 30 years, leading SCLC to be designated a 'recalcitrant cancer'. Scientific studies are hampered by a lack of tissue availability. However, over the past 5 years, there has been a worldwide resurgence of studies on SCLC, including comprehensive molecular analyses, the development of relevant genetically engineered mouse models and the establishment of patient-derived xenografts. These studies have led to the discovery of new potential therapeutic vulnerabilities for SCLC and therefore to new clinical trials. Thus, while the past has been bleak, the future offers greater promise.
519 citations
TL;DR: In this article, a combination of CRISPR-Cas9-based genetic screening and metabolomic analyses was used to identify mutations in the KEAP1 gene encoding Kelch-like ECH-associated protein 1 (KEAP1), a negative regulator of nuclear factor erythroid 2-like 2 (NFE2L2), which is the master transcriptional regulator of the endogenous antioxidant response.
Abstract: Treating KRAS-mutant lung adenocarcinoma (LUAD) remains a major challenge in cancer treatment given the difficulties associated with directly inhibiting the KRAS oncoprotein. One approach to addressing this challenge is to define mutations that frequently co-occur with those in KRAS, which themselves may lead to therapeutic vulnerabilities in tumors. Approximately 20% of KRAS-mutant LUAD tumors carry loss-of-function mutations in the KEAP1 gene encoding Kelch-like ECH-associated protein 1 (refs. 2, 3, 4), a negative regulator of nuclear factor erythroid 2-like 2 (NFE2L2; hereafter NRF2), which is the master transcriptional regulator of the endogenous antioxidant response. The high frequency of mutations in KEAP1 suggests an important role for the oxidative stress response in lung tumorigenesis. Using a CRISPR-Cas9-based approach in a mouse model of KRAS-driven LUAD, we examined the effects of Keap1 loss in lung cancer progression. We show that loss of Keap1 hyperactivates NRF2 and promotes KRAS-driven LUAD in mice. Through a combination of CRISPR-Cas9-based genetic screening and metabolomic analyses, we show that Keap1- or Nrf2-mutant cancers are dependent on increased glutaminolysis, and this property can be therapeutically exploited through the pharmacological inhibition of glutaminase. Finally, we provide a rationale for stratification of human patients with lung cancer harboring KRAS/KEAP1- or KRAS/NRF2-mutant lung tumors as likely to respond to glutaminase inhibition.
397 citations
14 Jan 2021
TL;DR: The recent introduction of immune checkpoint blockade into the treatment of patients with small-cell lung cancer (SCLC) is offering new hope, with a small subset of patients deriving prolonged benefit.
Abstract: Small-cell lung cancer (SCLC) represents about 15% of all lung cancers and is marked by an exceptionally high proliferative rate, strong predilection for early metastasis and poor prognosis. SCLC is strongly associated with exposure to tobacco carcinogens. Most patients have metastatic disease at diagnosis, with only one-third having earlier-stage disease that is amenable to potentially curative multimodality therapy. Genomic profiling of SCLC reveals extensive chromosomal rearrangements and a high mutation burden, almost always including functional inactivation of the tumour suppressor genes TP53 and RB1. Analyses of both human SCLC and murine models have defined subtypes of disease based on the relative expression of dominant transcriptional regulators and have also revealed substantial intratumoural heterogeneity. Aspects of this heterogeneity have been implicated in tumour evolution, metastasis and acquired therapeutic resistance. Although clinical progress in SCLC treatment has been notoriously slow, a better understanding of the biology of disease has uncovered novel vulnerabilities that might be amenable to targeted therapeutic approaches. The recent introduction of immune checkpoint blockade into the treatment of patients with SCLC is offering new hope, with a small subset of patients deriving prolonged benefit. Strategies to direct targeted therapies to those patients who are most likely to respond and to extend the durable benefit of effective antitumour immunity to a greater fraction of patients are urgently needed and are now being actively explored.
345 citations
TL;DR: A genome-wide CRISPR/Cas9 screen identified an evolutionarily conserved function of polycomb repressive complex 2 (PRC2) that mediates coordinated transcriptional silencing of the MHC-I antigen processing pathway (M HC-I APP), promoting evasion of T cell-mediated immunity.
312 citations
TL;DR: A single-cell chromatin immunoprecipitation followed by sequencing approach paves the way to study the role of chromatin heterogeneity, not just in cancer but in other diseases and healthy systems, notably during cellular differentiation and development.
Abstract: Modulation of chromatin structure via histone modification is a major epigenetic mechanism and regulator of gene expression. However, the contribution of chromatin features to tumor heterogeneity and evolution remains unknown. Here we describe a high-throughput droplet microfluidics platform to profile chromatin landscapes of thousands of cells at single-cell resolution. Using patient-derived xenograft models of acquired resistance to chemotherapy and targeted therapy in breast cancer, we found that a subset of cells within untreated drug-sensitive tumors share a common chromatin signature with resistant cells, undetectable using bulk approaches. These cells, and cells from the resistant tumors, have lost chromatin marks-H3K27me3, which is associated with stable transcriptional repression-for genes known to promote resistance to treatment. This single-cell chromatin immunoprecipitation followed by sequencing approach paves the way to study the role of chromatin heterogeneity, not just in cancer but in other diseases and healthy systems, notably during cellular differentiation and development.
303 citations
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TL;DR: A substantial proportion of the worldwide burden of cancer could be prevented through the application of existing cancer control knowledge and by implementing programs for tobacco control, vaccination, and early detection and treatment, as well as public health campaigns promoting physical activity and a healthier dietary intake.
Abstract: The global burden of cancer continues to increase largely because of the aging and growth of the world population alongside an increasing adoption of cancer-causing behaviors, particularly smoking, in economically developing countries. Based on the GLOBOCAN 2008 estimates, about 12.7 million cancer cases and 7.6 million cancer deaths are estimated to have occurred in 2008; of these, 56% of the cases and 64% of the deaths occurred in the economically developing world. Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among females, accounting for 23% of the total cancer cases and 14% of the cancer deaths. Lung cancer is the leading cancer site in males, comprising 17% of the total new cancer cases and 23% of the total cancer deaths. Breast cancer is now also the leading cause of cancer death among females in economically developing countries, a shift from the previous decade during which the most common cause of cancer death was cervical cancer. Further, the mortality burden for lung cancer among females in developing countries is as high as the burden for cervical cancer, with each accounting for 11% of the total female cancer deaths. Although overall cancer incidence rates in the developing world are half those seen in the developed world in both sexes, the overall cancer mortality rates are generally similar. Cancer survival tends to be poorer in developing countries, most likely because of a combination of a late stage at diagnosis and limited access to timely and standard treatment. A substantial proportion of the worldwide burden of cancer could be prevented through the application of existing cancer control knowledge and by implementing programs for tobacco control, vaccination (for liver and cervical cancers), and early detection and treatment, as well as public health campaigns promoting physical activity and a healthier dietary intake. Clinicians, public health professionals, and policy makers can play an active role in accelerating the application of such interventions globally.
52,293 citations
TL;DR: A substantial portion of cancer cases and deaths could be prevented by broadly applying effective prevention measures, such as tobacco control, vaccination, and the use of early detection tests.
Abstract: Cancer constitutes an enormous burden on society in more and less economically developed countries alike. The occurrence of cancer is increasing because of the growth and aging of the population, as well as an increasing prevalence of established risk factors such as smoking, overweight, physical inactivity, and changing reproductive patterns associated with urbanization and economic development. Based on GLOBOCAN estimates, about 14.1 million new cancer cases and 8.2 million deaths occurred in 2012 worldwide. Over the years, the burden has shifted to less developed countries, which currently account for about 57% of cases and 65% of cancer deaths worldwide. Lung cancer is the leading cause of cancer death among males in both more and less developed countries, and has surpassed breast cancer as the leading cause of cancer death among females in more developed countries; breast cancer remains the leading cause of cancer death among females in less developed countries. Other leading causes of cancer death in more developed countries include colorectal cancer among males and females and prostate cancer among males. In less developed countries, liver and stomach cancer among males and cervical cancer among females are also leading causes of cancer death. Although incidence rates for all cancers combined are nearly twice as high in more developed than in less developed countries in both males and females, mortality rates are only 8% to 15% higher in more developed countries. This disparity reflects regional differences in the mix of cancers, which is affected by risk factors and detection practices, and/or the availability of treatment. Risk factors associated with the leading causes of cancer death include tobacco use (lung, colorectal, stomach, and liver cancer), overweight/obesity and physical inactivity (breast and colorectal cancer), and infection (liver, stomach, and cervical cancer). A substantial portion of cancer cases and deaths could be prevented by broadly applying effective prevention measures, such as tobacco control, vaccination, and the use of early detection tests.
23,203 citations
"Chemosensitive Relapse in Small Cel..." refers background in this paper
...Small cell lung cancer (SCLC) affects an estimated 270,000 individuals per year worldwide and is metastatic at the time of diagnosis in approximately two-thirds of cases (Shepherd et al., 2007; Torre et al., 2015)....
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8,687 citations
"Chemosensitive Relapse in Small Cel..." refers methods in this paper
...8 using Youden’s index (Youden, 1950) did not show a statistically significant difference...
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...However, applying a dichotomized H score of 68.8 using Youden’s index (Youden, 1950) did not show a statistically significant difference in overall survival (p = 0.884, log rank test; Figure S4E)....
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Wellcome Trust Sanger Institute1, Cambridge University Hospitals NHS Foundation Trust2, Wellcome Trust3, University of British Columbia4, University of Cambridge5, Oslo University Hospital6, The Breast Cancer Research Foundation7, University of Oslo8, University of Münster9, Université libre de Bruxelles10, German Cancer Research Center11, University of Iceland12, Erasmus University Rotterdam13, Paris Descartes University14, French Institute of Health and Medical Research15, University of Paris16, Broad Institute17, University of Bergen18, University of Oviedo19, University of Queensland20, University of Glasgow21, Harvard University22, United States Department of Veterans Affairs23, Netherlands Cancer Institute24, University of Kiel25, Radboud University Nijmegen26, King's College London27, Curie Institute28, Bankstown Lidcombe Hospital29, University of New South Wales30, University of Barcelona31
TL;DR: It is shown that hypermutation localized to small genomic regions, ‘kataegis’, is found in many cancer types, and this results reveal the diversity of mutational processes underlying the development of cancer.
Abstract: All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, 'kataegis', is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.
7,904 citations
"Chemosensitive Relapse in Small Cel..." refers background in this paper
...A focused analysis on MSK-LX40 and MSK-LX95, two models with matched normal DNA, revealed the expected mutational pattern enriched in C > A transversions, consistent with the tobacco smoke-induced mutational signature (Alexandrov et al., 2013) (Figure 2B)....
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TL;DR: The results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents and the generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of ‘personalized’ therapeutic regimens.
Abstract: The systematic translation of cancer genomic data into knowledge of tumour biology and therapeutic possibilities remains challenging. Such efforts should be greatly aided by robust preclinical model systems that reflect the genomic diversity of human cancers and for which detailed genetic and pharmacological annotation is available. Here we describe the Cancer Cell Line Encyclopedia (CCLE): a compilation of gene expression, chromosomal copy number and massively parallel sequencing data from 947 human cancer cell lines. When coupled with pharmacological profiles for 24 anticancer drugs across 479 of the cell lines, this collection allowed identification of genetic, lineage, and gene-expression-based predictors of drug sensitivity. In addition to known predictors, we found that plasma cell lineage correlated with sensitivity to IGF1 receptor inhibitors; AHR expression was associated with MEK inhibitor efficacy in NRAS-mutant lines; and SLFN11 expression predicted sensitivity to topoisomerase inhibitors. Together, our results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents. The generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of 'personalized' therapeutic regimens.
6,417 citations