Abstract
A major barrier to achieving durable remission and definitive cure in oncology patients is the emergence of tumor resistance, a common outcome of different disease types independent from the ...therapeutic approach undertaken. Patients with pancreatic ductal adenocarcinoma (PDAC) continue to have a poor prognosis despite concerted efforts to advance new drugs to the clinic. One reason for this, in PDAC and other tumors, is that tumors are constantly adapting and evolving in response to external perturbations. To better investigate tumor evolution in response to therapy we developed a new clonal tracking platform that enables the in vivo study of long term self-renewing compartments and the generation of cohorts of patient-derived xenografts in which tumors are virtually identical and maintained by the same clones (clonal replica tumors), representing a unique tool to address fundamental questions about clonal dynamics in response to pharmacological treatment. Using this novel approach we demonstrate that standard of care in pancreatic cancer, despite inducing tumor regression, has minimal effect on the clonal composition of tumors that eventually relapse. Transcriptomic and metabolic characterization of residual tumor cells in patient derived xenograft models as well as in patients after chemoradiation shows that resistant cells that contribute to tumor relapse are metabolically rewired to upregulate mitochondrial respiration (OXPHOS). Combining a novel inhibitor of oxidative phosphorylation (IACS-010759), developed at the MD Anderson Institute for Applied Cancer Science and currently in phase I clinical trial in relapsed/refractory acute myelogenous leukemia and advanced solid tumors, with standard of care drugs drastically reduces tumor clonal complexity, underscoring the promise of inhibiting mitochondrial respiration as a new therapeutic strategy to prolong patient survival by eradicating resistant clones that survive chemoradiation.
Citation Format: Sara Loponte, Denise Corti, Sahil Seth, Edoardo Del Poggetto, I-Lin Ho, Chieh-Yuan Li, Shan Jiang, Joseph R. Marszalek, Maria Emilia Di Francesco, Giannicola Genovese, Giulio Draetta, Alessandro Carugo, Andrea Viale. Metabolic targeting of chemoresistance perturbs clonal complexity in pancreatic cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4953.
Abstract
Tumor evolution and adaptation, especially in response to therapy, are well-established concepts in clinical oncology and a major causes of treatment failure. The inability of current ...experimental models, including genetically engineered mouse models, to inform on the breadth of functional heterogeneity within human tumors has substantially limited our understanding of the evolution of tumor architecture under perturbations such as pharmacologic treatments with a profound negative impact on cancer drug discovery research, where drug efficacy continues to be measured in terms of tumor volume.
To address this technologic gap, we developed a new approach based on clonal tracking to model human tumors in vivo supporting the dissection of functional heterogeneity at the clonal level as well as the study of tumor evolution and clonal dynamics in response to external perturbations in real time. Lentivirus-based systems have been extensively used as a tool to investigate the clonal dynamics and tumor cell heterogeneities of solid tumors, but they have been limited by a lack of sensitivity and the impossibility of tracking identical clones in different animals. Using a revised strategy to barcode patient-derived pancreatic cancer cells coupled with deep-sequencing analysis, we created PDX cohorts harboring Clonal Replica Tumors (hereafter CRTs), in which all mice bear human tumors maintained by the same clones. Because they are maintained by thousands of common clones and are virtually identical, CRTs enable the evaluation of single- and combined-therapy approaches as well as mechanistic studies where the evolution and dynamics of single clones can be tracked with extremely high precision to monitor the contribution of even low-represented clones to tumor growth and relapse. Since functional heterogeneity in tumors can only be fully appreciated upon different perturbations, the availability of large cohorts of animals bearing clonally identical tumors makes CRTs a critical instrument to investigate tumor complexity in vivo. Further, another advancement supported by the CRT platform is the isolation and expansion of any clone of interest identified in vivo through bioinformatics analysis. High-throughput isolation and functional characterization of virtually every clonal population of cells within a CRT provides an invaluable tool to identify exploitable vulnerabilities of resistant clones.
In conclusion, CRTs represent an innovative approach to dissect the complexity of human tumors at an unprecedented level of resolution, enabling the investigation of mechanisms of tumor evolution and drug resistance. Understanding clonal dynamics, tumor composition, and adaptive mechanisms, and how these factors may influence treatment response, is essential to reach new horizons in cancer care.
Citation Format: Sahil Seth, Chieh-Yuan Li, Denise Corti, Sara Loponte, I-Lin Ho, Edoardo Del Poggetto, Michael Peoples, Christopher Bristow, Joseph Marszalek, Timothy Heffernan, Giannicola Genovese, Giulio Draetta, Alessandro Carugo, Andrea Viale. Generation of clonal replica tumors to interrogate complexity of human cancer in vivo abstract. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A15.
Abstract
Half of all triple negative breast cancer (TNBC) patients harbor significant residual cancer burden following standard neoadjuvant chemotherapy treatment, resulting in distant metastasis and ...death for most of these patients. Intra-tumor heterogeneity (ITH) is pervasive in TNBC as is a barrier to development of effective therapeutic strategies, but the relative contributions of heterogeneous tumor cell populations to chemoresistance and metastasis are not well understood. To investigate the clonal dynamics that accompany chemotherapy treatment and metastasis, we employed orthotopic patient-derived xenograft (PDX) models of treatment-naïve TNBC, thus enabling experimentation with heterogeneous populations of human tumor cells that have undergone minimal manipulation.
To monitor the fates of PDX tumor cell lineages as they metastasized, we introduced a pooled lentiviral barcode library (Cellecta) into freshly dissociated PDX tumor cells which were orthotopically engrafted into recipient mice. Genomic analyses, including barcode enumeration, whole-exome sequencing, custom targeted DNA sequencing, and transcriptome sequencing, were conducted to characterize the clonal dynamics that accompanied metastasis. Of the thousands of diverse primary tumor clones, only ~2% harbored metastatic capacity. Of those, a rare population of the exact same clones predominated metastases in lung, liver, and brain, the three most common sites of human TNBC metastasis. These studies provide a quantitative map of the clonal architecture of multi-organ metastasis in TNBC and reveal that identical subclones can thrive in diverse secondary organ microenvironments.
NACT resistance leads to metastasis and death for most patients, yet the origins of chemoresistance in TNBC are unclear. We modeled NACT resistance in an array of PDX models derived from treatment-naïve TNBC biopsies in alignment with an ongoing neoadjuvant clinical trial (NCT02276443). Upon partial response to NACT, tumors entered a transient drug-tolerant state characterized by distinct histologic, proteomic, and transcriptomic features that were reverted as tumors regrew after cessation of treatment. Barcode-mediated lineage tracking and whole-exome sequencing revealed that the drug-tolerant state was not mediated by clonal selection. Based on transcriptomic and metabolic features of the drug-tolerant state, we conducted preclinical trials with an inhibitor of mitochondrial oxidative phosphorylation (IACS-010759), which significantly delayed the regrowth of residual tumors in PDX models. Together, these studies revealed that TNBCs can resist NACT through non-selective adaptation of a reversible phenotypic state, and that inhibition of oxidative phosphorylation may be a promising therapy in the neoadjuvant setting for TNBC.
Citation Format: Gloria V. Echeverria, Zhongqi Ge, Sahil Seth, Emily Powell, Xiaomei Zhang, Sabrina Jeter-Jones, Xinhui Zhou, Yan Jiang, Aaron McCoy, Shirong Cai, Yizheng Tu, Michael Peoples, Yuting Sun, Huan Qiu, Christopher Bristow, Alessandro Carugo, Jiansu Shao, Stacy L. Moulder, William F. Symmans, Timothy P. Heffernan, Jeffrey T. Chang, Helen M. Piwnica-Worms. Clonal dynamics and phenotypic evolution during chemoresistance and metastasis revealed by patient-derived xenograft models of triple negative breast cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2901.
Abstract
Adaptive drug-resistance mechanisms allow human tumors to evade treatment through selection and expansion of treatment-resistant clones. Modeling the functional heterogeneity of tumors can ...unmask critical contributions of distinct tumor cell sub-populations toward identifying rational drug combinations. Here, studying clonal evolution of tumor cells derived from human pancreatic tumors, we demonstrate that in vitro adherent cultures and in vivo tumors are maintained by a common set of long term self-renewing tumorigenic cells that can be used to establish clonal replica tumors (CRTs), large cohorts of animals bearing human tumors with identical clonal composition. Using CRTs to conduct quantitative assessments of clonal dynamics and adaptive responses to therapeutic challenge over time, we uncovered that the tumorigenic compartment of pancreatic tumors maintains a multitude of functionally heterogeneous subpopulations of cells with differential degrees of sensitivity to therapeutics. High-throughput isolation and deep characterization of unique clonal lineages showed genetic and transcriptomic diversity underlying the functionally diverse subpopulations, positioning the origins of tumor heterogeneity within the long-term self-renewing compartment. Molecular annotation of gemcitabine-naïve clonal lineages with distinct responses to treatment in the context of CRTs generated signatures that can predict the response to chemotherapy and exposed pre-existing functional mechanisms of clonal resistance, primarily associated to DNA damage tolerance and mitochondrial respiration (OXPHOS). Further transcriptomic and metabolic characterization of residual tumor cells in patient derived xenograft models as well as in patients after chemoradiation showed that resistant cells that contribute to tumor relapse are metabolically rewired to upregulate OXPHOS. Combining a novel inhibitor of oxidative phosphorylation (IACS-10759) developed at the MD Anderson Institute for Applied Cancer Science, and currently in phase I clinical trial in acute myeloid leukemia and solid tumors, with standard of care drugs drastically reduces tumor clonal complexity, underscoring the promise of inhibiting mitochondrial respiration as a new therapeutic strategy to prolong patient survival by eradicating resistant clones that survive chemoradiation. Our study, correlating genomic and transcriptomic traits with specific functional phenotypes, uncovered new mechanisms that underlie intra-tumor sub-clonal heterogeneity, influence treatment response to drugs and sustain tumor relapse.
Citation Format: Sahil Seth, Chieh-Yuan Li, Sara Loponte, I-Lin Ho, Denise Corti, Luigi Sapio, Edoardo Del Poggetto, Michael Peoples, Tatiana Karpinets, Frederick S. Robinson, Shan Jiang, Prasanta Dutta, Joseph Marszalek, Maria E. Di Francesco, Timothy P. Heffernan, Virginia Giuliani, Pratip K. Bhattacharya, Giannicola Genovese, Andrew Futreal, Giulio Draetta, Andrea Viale, Alessandro Carugo. Dissection of clonal heterogeneity unmasks pre-existing chemoresistance and new metabolic vulnerabilities in pancreatic cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2900.
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Background: Androgen-receptor-like (LAR) triple-negative breast cancer (TNBC) is a subtype identified using Vanderbilt’s molecular signature. LAR subtype has the lowest pCR rate for ...NACT among all TNBC subtypes (10% vs. 28% for TNBC in general). We launched a clinical trial to determine the effectiveness of enzalutamide and paclitaxel (ZT) in improving this poor chemo. response in the neoadjuvant setting for pts with anthracycline-refractory, androgen receptor (AR)+ TNBC (NCT02689427). However, we do not yet have a robust predictive biomarker to detect an activated AR pathway and have not seen a robust correlation between molecular LAR subtype and AR IHC staining intensity. Methods: Molecular profiling and immunohistochemical analysis of key biomarkers (LAR, Ki67, and vimentin) was performed for all pts enrolled in A Randomized triple negative breast cancer enrolling Trial to Confirm Molecular Profiling Improves Survival (ARTEMIS; NCT02276443). Patients receive 4 cycles of AC, followed by an experimental arm or standard taxane, tailored using nuclear IHC staining. IHC staining of ≥30% AR+ was used as a threshold for selection for enzalutamide combination arm. We evaluated the concordance between LAR-subtype using molecular profiling vs % AR+ cells via IHC. Results: As part of the clinical trial, tumors with ≥30% AR+ cells were classified as LAR. In addition, we used RNA profiling to assign Vanderbilt subtype scores, resulting in classification of 15 tumors as LAR+. We observed a significant correlation (r=0.75) between LAR score and %AR+ cells, with 13 of 15 LAR tumors having ≥30% AR+ cells. Among patients with high % of AR+ tumor cells, 11 received enzalutamide, with 43% (3/7) having responses (pCR or RCB-I). Conclusions: Comparison on numerical scores for Vanderbilt subtype and IHC scores suggests ≥30% AR+ IHC staining as the threshold (ppv=0.65, npv=0.98, Table) to identify the molecular LAR subtype. We observed a trend where response rate was higher in patients with ≥ AR+ IHC scores treated with enzalutamide; however, these results need confirmation in a larger cohort of patients. Clinical trial information: NCT02689427, NCT02276443. Table: see text
Src homology 2 domain-containing phosphatase (SHP2) is a phosphatase that mediates signaling downstream of multiple receptor tyrosine kinases (RTK) and is required for full activation of the MAPK ...pathway. SHP2 inhibition has demonstrated tumor growth inhibition in RTK-activated cancers in preclinical studies. The long-term effectiveness of tyrosine kinase inhibitors (TKI) such as the EGFR inhibitor osimertinib in non-small cell lung cancer (NSCLC) is limited by acquired resistance. Multiple clinically identified mechanisms underlie resistance to osimertinib, including mutations in EGFR that preclude drug binding as well as EGFR-independent activation of the MAPK pathway through alternate RTK (RTK-bypass). It has also been noted that frequently a tumor from a single patient harbors more than one resistance mechanism and the plasticity between multiple resistance mechanisms could restrict the effectiveness of therapies targeting a single node of the oncogenic signaling network. Here we report the discovery of IACS-13909, a specific and potent allosteric inhibitor of SHP2 that suppresses signaling through the MAPK pathway. IACS-13909 potently impeded proliferation of tumors harboring a broad spectrum of activated RTK as the oncogenic driver. In EGFR
mut
osimertinib-resistant NSCLC models with EGFR-dependent and EGFR-independent resistance mechanisms, IACS-13909, administered as a single agent or in combination with osimertinib, potently suppressed tumor cell proliferation
in vitro
and caused tumor regression
in vivo
. Together, our findings provide preclinical evidence for using a SHP2 inhibitor as a therapeutic strategy in acquired EGFR inhibitor-resistant NSCLC.
Abstract
Comprehensive characterization of genomic alterations prevalent in head and neck squamous cell carcinoma (HNSCC) has been performed by our group and others, and more recently by The Cancer ...Genome Atlas (TCGA) project. A significant barrier towards targeting the genomic alterations collectively found in HNSCC is that the genomic landscape of this disease is dominated by mutations to tumor suppressor genes that are inherently difficult to target, with very few mutated oncogenes present. Although potentially targetable oncogenic drivers may exist within chromosomal regions of copy number gain, the large number of genes within these regions makes identifying the precise targets challenging. To overcome some of these difficulties, we have been leveraging high throughput loss of function shRNA screens performed in vivo in order to identify co-dependencies and potential ways to target genomic alterations in HNSCC. Using a large panel of genomically characterized established HNSCC cell lines in conjunction with several different shRNA libraries, including ones that target druggable genes (i.e. FDAome), genes involved in DNA repair, and candidate HNSCC driver genes, we hope to link shRNA targets that are vital for in vivo growth and survival to specific genomic subtypes present within HNSCC. Following pooled in vitro infection with these libraries, HNSCC cell lines are injected into the flanks of mice where in vivo selection takes place, and dropout of barcoded shRNAs targeting genes advantageous for tumor growth is subsequently analyzed from harvested tumors by next generation sequencing. The FDAome library contains shRNAs to nearly 200 genes immediately targetable by FDA approved drugs, allowing identification of druggable co-dependent pathways through simple lethality. By comparing dropout of shRNAs from tumors of mice treated with or without carboplatin, genes that chemosensitize tumors in vivo are also being identified within the FDAome and DNA repair shRNA libraries. Screens performed with our custom HNSCC shRNAs library targeting many genes from regions recurrently amplified in large subsets of patient tumors should identify which genes within these regions are true drivers and potentially interesting drug candidates. Thus far, we have completed in vivo screens employing the FDAome and DNA damage libraries on four different HNSCC cell lines, comprised of 3 different NOTCH1 mutants and one NOTCH1 wild type cell line, which collectively include two HPV-positive and two HPV-negative cell lines. Data analysis has identified a number of druggable targets that inhibit the growth of NOTCH1 mutant cell lines or that seem to be specific for HPV+ tumors. Some of these targets have been further validated through in vivo experiments employing single shRNAs to genes of interest, employing targeting sequences distinct from the libraries. The growth inhibitory effects for some of the hits are apparent in vivo, but not in vitro, highlighting the ability of this unique platform to identify genes or pathways that drive the three-dimensional growth of tumors in the microenvironment of the host. We have also completed an in vivo screen on two of the cell lines using the custom shRNA library that targets genes recurrently amplified in HNSCC, and are currently analyzing data. Preliminary analysis indicates that this high throughput in vivo shRNA screening platform is a promising and relevant approach for identifying co-dependencies and ways to target genomic alterations in cancer.
Citation Format: Tongxin Xie, Ramya L. Parimi, Manish F. Kumar, Liang P. Yang, Jiping Wang, Sahil Seth, Carugo Alessandro, Christopher A. Bristow, Frederick Scott Robinson, Michael D. Peoples, Heath Skinner, Jeffrey N. Myers, Curtis R. Pickering, Mitchell J. Frederick. An in vivo high throughput shRNA screening platform for identifying ways to target genomic alterations abstract. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr IA12.
Abstract
Large-scale genomics efforts have provided the opportunity to access a comprehensive catalog of genetic alterations in multiple cancers. However, it has also become apparent that very few ...driver mutations are emerging and as a consequence of that, limited opportunities exist to target mutated oncogenic proteins. It is imperative therefore to develop alternative approaches to therapy that can leverage the selective vulnerabilities of tumor cells resulting from the engagement of abnormal pathway connectivity. These can be best exploited in vivo, in a context that is closer to the environment tumors strive in. To identify new relevant actionable dependencies we have developed PILOT (Patient-oriented In vivo Lethality to Optimize Treatment), a loss-of-function in vivo platform for rapid identification of potential therapeutic targets in Patient-Derived Xenografts (PDXs). By optimizing primary tumor explant and expansion, determination of tumor-initiating cell frequency trough retroviral-mediated transduction, in vivo RNA interference screens, next-generation sequencing and analytic pipelines, we have been able to establish a comprehensive “patient-centric” approach oriented towards the identification of the highest priority genetic targets in specific clinico-pathological and mutational settings. So far, the main limitation for the systematic exploitation of in vivo functional genomics systems to elucidate patient vulnerabilities in the PDX models come from the limited number of human cells contributing to tumor establishment in a transplantation setting. The frequency of these tumors initiating cells (TICs) is commonly estimated by time-consuming limiting dilution assays and may consistently vary between different tumor origins. With this in mind, we have integrated in our platform a system based on scrambled barcoded libraries that allows to directly assess the required coverage of screening libraries in each model and adjust the RNAi screens for this factor. Our coverage study demonstrated to be a powerful tool to identify the minimal number of cells/barcode required to sustain a complex library in PDX models and at the same time a step forward to personalize the in vivo screening patient-by-patient. As proof of concept, we applied our PILOT platform to systematically interrogate context-specific epigenetic dependencies in pancreatic ductal adenocarcinoma (PDAC). In addition to the well-known genetic alterations (KRAS, TP53, CDKN2A/p16, SMAD4), some epigenetic mechanisms demonstrated to play a central role in PDAC progression and some of them could intriguingly represent new points of vulnerability, due to the low-frequency of mutation (ex. collateral or synthetic lethality). Our screening system utilized fully annotated low-passage PDAC xenografts and a lentiviral library of pooled shRNAs targeting 230 potentially “druggable” epigenetic regulators adjusted for the coverage study in each PDX. Hairpin-associated molecular barcodes were quantified by massively parallel sequencing and clustered according to their depletion or enrichment in comparison to a control population before transplantation. To date, we have completed a total of 5 in vivo screens using diverse PDAC xenograft models and, applying our comprehensive mutational and functional data analytics pipeline, we have developed a high-throughput validation scheme to triage “hits” that emerge from each screen. Focusing on epigenetic regulators, we identified WDR5, a core member of the COMPASS histone H3 Lys4 (H3K4) MLL (1-4) methyltransferase complex, as a top tumor maintenance hit required across multiple PDAC tumors and associated with the presence of G1-checkpoint alterations (p53 or p16). Mechanistically, WDR5 functions to sustain proper execution of DNA replication in PDAC cells, as previously suggested by replication stress studies involving MLL1, a critical ATR substrate, and c-Myc, also found to interact with WDR5. We indeed demonstrated that the WDR5-Myc interaction is critical for this replicative function and protects the PDAC cells from the excessive DNA damage accumulation and mitotic catastrophe. Intriguingly, this checkpoint function executed by the WDR5-Myc axis to protect the S-phase seems to be an addiction of the cancer cells, that have more active replication forks to stabilize in order to sustain the abnormal proliferative burst. To confirm this new cancer-associated lethality, we demonstrated that normal cells display less sensitivity to this replication checkpoint in virtue of their proficient G1-checkpoints and reduced time spent in S-phase compared to cancer cells. So, our PILOT platform was able to illuminate new therapeutic vulnerabilities that can be rapidly evaluated in the clinic through the development of WDR5-Myc inhibitors. In the near future, we plan to extend this platform in syngeneic mouse models, where one can probe the effects of target inhibition in the context of an intact immune response and in the presence of immune checkpoint activators, and in association with approved drugs, to identify new therapeutic options for recalcitrant tumor populations.
Citation Format: Alessandro Carugo, Giannicola Genovese, Sahil Seth, Luigi Nezi, Angelo Cicalese, Daniela Bossi, Johnathon L. Rose, Andrea Viale, Luisa Lanfrancone, Timothy P. Heffernan, Giulio F. Draetta. PILOT: a patient-oriented in vivo functional platform to identify new lethalities and optimize cancer treatment. abstract. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B43.
Abstract
Head and neck squamous cell carcinoma (HNSCC) is a diverse group of tumors from the upper aerodigestive tract that are treated primarily with surgery, chemotherapy, and/or radiation. Recent ...genomic studies have characterized the genomic alterations in HNSCC but they failed to identify novel oncogenic drivers for therapeutic targeting. In order to identify novel targets we have utilized an in vivo shRNA library screening platform in a panel of genomically characterized HNSCC cell lines. The screens were performed alone or in combination with platinum-based chemotherapy or radiation, and the screening libraries included known druggable targets, DNA repair genes, and HNSCC candidate driver genes. Initial results indicate that this in vivo screening is able to identify targets that may not be found through traditional in vitro screening approaches and related to tumor-stromal interactions and metabolism. These genes emphasize the importance of including the tumor microenvironment in studies to understand driver genes and identify novel therapeutic interventions.
Citation Format: Curtis R. Pickering, Tongxin Xie, Manish Kumar, Ramya L. Parimi, Liang P. Yang, Jiping Wang, Sahil Seth, Christopher A. Bristow, Alessandro Carugo, Frederick S. Robinson, Giulio F. Draetta, Heath Skinner, Mitchell J. Frederick, Jeffrey N. Myers. In vivo shRNA library screening to identify novel targets for head and neck squamous cell carcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 415. doi:10.1158/1538-7445.AM2017-415
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e20058
Background: The sarcomatoid carcinoma of the lung (SCL) is a rare subtype of non-small cell lung cancers (NSCLC). The prognosis of SCL is poor with 5-year survival of ~20%. There ...have been only a few studies on genomic landscape of SCL. Comprehensive genomic and transcriptomic profiles of SCL have not been systematically studied. Methods: In this study, we performed whole-exome sequencing and ultra-deep targeted sequencing of 400 cancer genes on 21 resected localized SCLs and matched normal lung tissues. RNA sequencing (RNA-seq) was also performed to 17 SCLs and matched normal lung tissues for those with materials available. Results: On average, 688 mutations including 503 non-synonymous mutations were identified per tumor. Canonical cancer gene analysis demonstrated that the most frequently mutated gene in this cohort was TP53 (detected in 11 out of the 21 tumors) followed by KRAS (detected in 6 out of the 21 patients). The recently discovered potentially targetable MET exon 14-skipping mutation was also detected in 3 patients in our cohort. For the 17 tumors, for, whom RNA-seq was conducted, unsupervised clustering analysis using non-negative matrix factorization (NMF) led to two stable clusters of patients in our cohort. Of particular interest, all patients (7/7) in Cluster 1 have relapsed, while only 3 of 10 patients in Cluster 2 relapsed (p-value < 0.01). Further pathway analyses demonstrated that immune activation pathways are significantly up regulated in tumors from Cluster 2 compared to Cluster 1. Conclusions: SCLs seem to have similar genomic landscape and canonical cancer gene mutations compared to other types of NSCLCs such as squamous cell carcinoma and adenocarcinomas. Immune pathway activation may be associated with lower risk of postsurgical recurrence in patients with localized SCL.
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