<div>AbstractSNPs occur within chromatin-modulating factors; however, little is known about how these variants within the coding sequence affect cancer progression or treatment. Therefore, there is a need to establish their biochemical and/or molecular contribution, their use in subclassifying patients, and their impact on therapeutic response. In this report, we demonstrate that coding SNP-A482 within the lysine tridemethylase gene KDM4A/JMJD2A has different allelic frequencies across ethnic populations, associates with differential outcome in patients with non–small cell lung cancer (NSCLC), and promotes KDM4A protein turnover. Using an unbiased drug screen against 87 preclinical and clinical compounds, we demonstrate that homozygous SNP-A482 cells have increased mTOR inhibitor sensitivity. mTOR inhibitors significantly reduce SNP-A482 protein levels, which parallels the increased drug sensitivity observed with KDM4A depletion. Our data emphasize the importance of using variant status as candidate biomarkers and highlight the importance of studying SNPs in chromatin modifiers to achieve better targeted therapy.Significance: This report documents the first coding SNP within a lysine demethylase that associates with worse outcome in patients with NSCLC. We demonstrate that this coding SNP alters the protein turnover and associates with increased mTOR inhibitor sensitivity, which identifies a candidate biomarker for mTOR inhibitor therapy and a therapeutic target for combination therapy. Cancer Discov; 5(3); 245–54. ©2015 AACR.See related commentary by Rothbart et al., p. 228See related article by Van Rechem et al., p. 255This article is highlighted in the In This Issue feature, p. 213</div>

Demethylase

10.1158/2159-8290.c.6546149

Cite

Citations (0)

Data from PTEN Loss Mediates Clinical Cross-Resistance to CDK4/6 and PI3Kα Inhibitors in Breast Cancer

Carlotta Costa Ye Wang Amy Ly Yasuyuki Hosono Ellen Murchie

<div>AbstractThe combination of CDK4/6 inhibitors with antiestrogen therapies significantly improves clinical outcomes in ER-positive advanced breast cancer. To identify mechanisms of acquired resistance, we analyzed serial biopsies and rapid autopsies from patients treated with the combination of the CDK4/6 inhibitor ribociclib with letrozole. This study revealed that some resistant tumors acquired RB loss, whereas other tumors lost PTEN expression at the time of progression. In breast cancer cells, ablation of PTEN, through increased AKT activation, was sufficient to promote resistance to CDK4/6 inhibition in vitro and in vivo. Mechanistically, PTEN loss resulted in exclusion of p27 from the nucleus, leading to increased activation of both CDK4 and CDK2. Because PTEN loss also causes resistance to PI3Kα inhibitors, currently approved in the post-CDK4/6 setting, these findings provide critical insight into how this single genetic event may cause clinical cross-resistance to multiple targeted therapies in the same patient, with implications for optimal treatment-sequencing strategies.Significance:Our analysis of serial biopsies uncovered RB and PTEN loss as mechanisms of acquired resistance to CDK4/6 inhibitors, utilized as first-line treatment for ER-positive advanced breast cancer. Importantly, these findings have near-term clinical relevance because PTEN loss also limits the efficacy of PI3Kα inhibitors currently approved in the post-CDK4/6 setting.This article is highlighted in the In This Issue feature, p. 1</div>

10.1158/2159-8290.c.6545883

Cite

Citations (0)

Data from STAT3 Plays a Critical Role in KRAS-Induced Pancreatic Tumorigenesis

Ryan B. Corcoran Gianmarco Contino Vikram Deshpande Alexandros Tzatsos Claudius Conrad

<div>AbstractThe STAT3 transcription factor is an important regulator of stem cell self-renewal, cancer cell survival, and inflammation. In the pancreas, STAT3 is dispensable for normal development, whereas the majority of pancreatic ductal adenocarcinomas (PDAC) show constitutive activation of STAT3, suggesting its potential as a therapeutic target in this cancer. Here, we sought to define the mechanisms of STAT3 activation and its functional importance in PDAC pathogenesis. Large-scale screening of cancer cell lines with a JAK2 inhibitor that blocks STAT3 function revealed a more than 30-fold range in sensitivity in PDAC, and showed a close correlation of sensitivity with levels of tyrosine-phosphorylated STAT3 and of the gp130 receptor, an upstream signaling component. Correspondingly, upregulation of the IL6/LIF-gp130 pathway accounted for the strong STAT3 activation in PDAC subsets. To define functions of STAT3 in vivo, we developed mouse models that test the impact of conditional inactivation of STAT3 in KRAS-driven PDAC. We showed that STAT3 is required for the development of the earliest premalignant pancreatic lesions, acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN). Moreover, acute STAT3 inactivation blocked PDAC initiation in a second in vivo model. Our results show that STAT3 has critical roles throughout the course of PDAC pathogenesis, supporting the development of therapeutic approaches targeting this pathway. Moreover, our work suggests that gp130 and phospho-STAT3 expression may be effective biomarkers for predicting response to JAK2 inhibitors. Cancer Res; 71(14); 5020–9. ©2011 AACR.</div>

10.1158/0008-5472.c.6502293.v1

Cite

Citations (0)

Primary Patient-Derived Cancer Cells and Their Potential for Personalized Cancer Patient Care

Cell Reports (2017)

David P. Kodack Anna F. Farago Anahita Dastur Matthew A. Held Leila Dardaei

Personalized cancer therapy is based on a patient's tumor lineage, histopathology, expression analyses, and/or tumor DNA or RNA analysis. Here, we aim to develop an in vitro functional assay of a patient's living cancer cells that could complement these approaches. We present methods for developing cell cultures from tumor biopsies and identify the types of samples and culture conditions associated with higher efficiency of model establishment. Toward the application of patient-derived cell cultures for personalized care, we established an immunofluorescence-based functional assay that quantifies cancer cell responses to targeted therapy in mixed cell cultures. Assaying patient-derived lung cancer cultures with this method showed promise in modeling patient response for diagnostic use. This platform should allow for the development of co-clinical trial studies to prospectively test the value of drug profiling on tumor-biopsy-derived cultures to direct patient care.

10.1016/j.celrep.2017.11.051

Cite

Citations (182)

Abstract C201: Transposon activation mutagenesis as a screening tool for identifying resistance to cancer therapeutics.

Molecular Cancer Therapeutics (2013)

Lixia Chen Anahita Dastur Cyril H. Benes

Abstract The development of resistance to chemotherapies represents a significant barrier to successful cancer treatment. Resistance mechanisms are complex, can involve diverse and often unexpected cellular processes, and can vary with both the underlying genetic lesion and the origin or type of tumor. For these reasons developing experimental strategies that could be used to understand, identify and predict mechanisms of resistance in different malignant cells would be a major advance. Here we describe a novel gain-of-function forward genetic approach for identifying potential mechanisms of resistance. This system uses a modified piggyBac transposon to generate libraries of mutagenized cells, each containing transposon insertions that randomly activates nearby gene expression. By combining this with high-throughput sequencing, we have performed genome-wide screens for paclitaxel resistance mechanism in a variety of cancer cell lines. Validating this approach, we identified the multidrug transporter ABCB1 as the major contributor to resistance. In addition, we identified several potential novel resistance genes. Therefore we have developed a powerful new pipeline tool to systematically discover common and tumor specific pathways of resistance in human cancers. This cost-effective approach can be readily applied to different cell lines. Moreover, its ability to identify gene interactions and to probe complex genetic context provides a significant advantage over RNAi- or cDNA-based screens. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C201. Citation Format: Li Chen, Anahita Dastur, Cyril Benes. Transposon activation mutagenesis as a screening tool for identifying resistance to cancer therapeutics. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C201.

Genetic screen

Transposon mutagenesis

Insertional mutagenesis

10.1158/1535-7163.targ-13-c201

Cite

Citations (0)

Supplementary Figure 4 from EGFR-Mediated Chromatin Condensation Protects KRAS-Mutant Cancer Cells against Ionizing Radiation

Meng Wang Ashley M. Kern Marieke Hülskötter Patricia Greninger Anurag K. Singh

PDF file - 129KB, Effects of EGFR inhibition on regulation of senescence and apoptosis.

10.1158/0008-5472.22399577

Cite

Citations (0)

Supplementary tables from Preclinical Anticancer Efficacy of BET Bromodomain Inhibitors Is Determined by the Apoptotic Response

Andrew R. Conery Richard C. Centore Kerry L. Spillane Nicole E. Follmer Archana Bommi‐Reddy

This file contains 4 supplementary tables: Table S1 provides the expression values of the indicated genes (RMA) in BETi sensitive and insensitive cell lines; Table S2 shows the enrichment of subtypes of cell lines following selection with the indicated criteria; Table S3 shows SNP analysis of parental and BETi tolerant A375 cells; Table S4 shows SNP analysis of parental and BETi tolerant NOMO-1 cells.

Table (database)

SNP

10.1158/0008-5472.22409195

Cite

Citations (0)

Suppl. Table 1 from Oligosaccharyltransferase Inhibition Overcomes Therapeutic Resistance to EGFR Tyrosine Kinase Inhibitors

Cecilia López Sambrooks Marta Baro Amanda Quijano Azeet Narayan Wei Cui

Results of the Lung Cancer Cell Line Screen for OST Inhibitor Sensitivity

10.1158/0008-5472.22426452

Cite

Citations (0)

Data S1 from KRAS G12C NSCLC Models Are Sensitive to Direct Targeting of KRAS in Combination with PI3K Inhibition

Sandra Misale Jackson P. Fatherree Eliane Cortez Chendi Li Samantha Bilton

Supplementary Data 1

10.1158/1078-0432.22475840.v1

Cite

Citations (0)