Adapting a Drug Screening Platform to Discover Associations of Molecular Targeted Radiosensitizers with Genomic Biomarkers

Liu, Qi; Wang, Meng; Kern, Ashley M.; Khaled, Saman; Han, Jing; Yeap, Beow Y.; Hong, Theodore S.; Settleman, Jeff; Benes, Cyril H.; Held, Kathryn D.; Efstathiou, Jason A.; Willers, Henning

doi:10.1158/1541-7786.mcr-14-0570

Cited by 35 publications

(57 citation statements)

References 45 publications

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“…Annotated NSCLC cell lines were originally obtained from the MGH/Sanger cancer cell line collection http://www.cancerrxgene.org/translation/CellLine in the time period 2009–10, with the exception of A549 cells which were purchased from ATCC, as described in detail in previous publications (27, 29). Cell cultures were passaged for < 3 months after thawing an individual frozen vial.…”

Section: Methodsmentioning

confidence: 99%

“…The identity of the cell lines had been tested as described using a set of 16 short tandem repeats (STR) (AmpFLSTR Identifier KIT, ABI). In addition, single nucleotide polymorphism (SNP) profiles based on a panel of 63 SNPs assayed using the Sequenom Genetic Analyzer was used for in-house identity checking whenever a cell line was propagated and confirmed uniqueness of cell lines for the ones without available STR (27, 29). On some cell lines additional authentication was performed by Bio-Synthesis, Inc (Lewisville, TX).…”

Section: Methodsmentioning

confidence: 99%

“…Clonogenic survival assays were performed as previously published (29). Determination of cell numbers at 3 or 5 days after irradiation was performed by using a fluorescent nucleic acid stain Syto60 or CellTiter-Glo (CTG) luminescence assay (Promega, Madison, WI), respectively, as described (29).…”

Section: Methodsmentioning

confidence: 99%

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Radiation Resistance in KRAS-Mutated Lung Cancer Is Enabled by Stem-like Properties Mediated by an Osteopontin–EGFR Pathway

et al. 2017

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Lung cancers with activating KRAS mutations are characterized by treatment resistance and poor prognosis. In particular, the basis for their resistance to radiation therapy is poorly understood. Here we describe a radiation resistance phenotype conferred by a stem-like subpopulation characterized by mitosis-like condensed chromatin (MLCC), high CD133 expression, invasive potential, and tumor-initiating properties. Mechanistic investigations defined a pathway involving osteopontin and the EGFR in promoting this phenotype. Osteopontin/EGFR-dependent MLCC protected cells against radiation-induced DNA double-strand breaks and repressed putative negative regulators of stem-like properties such as CRMP1 and BIM. The MLCC-positive phenotype defined a subset of KRAS-mutated lung cancers that were enriched for co-occurring genomic alterations in TP53 and CDKN2A. Our results illuminate the basis for the radiation resistance of KRAS-mutated lung cancers with possible implications for prognostic and therapeutic strategies.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Radiation Resistance in KRAS-Mutated Lung Cancer Is Enabled by Stem-like Properties Mediated by an Osteopontin–EGFR Pathway

et al. 2017

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“…Liu et al reported an automated high-throughput (HTS) drug-screening platform (Figure 3) (27) based on short-term cell proliferation/survival assays (3-5 days incubation). These assays were used to derive a Short-term Radiosensitization Factor at 2 Gy (SRF 2Gy ), which correlates with standard Dose Enhancement Factors (DEF) derived from clonogenic survival assays using radiation doses up to 8 Gy.…”

Section: Focus Areas: Preclinical Radiobiological Assaysmentioning

confidence: 99%

Improving the Predictive Value of Preclinical Studies in Support of Radiotherapy Clinical Trials

Coleman

Higgins

Brown

et al. 2016

Clinical Cancer Research

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There is an urgent need to improve reproducibility and translatability of preclinical data in order to fully exploit opportunities for molecular therapeutics involving radiation and radio-chemotherapy. For in vitro the clonogenic assay remains the current state-of-the-art of preclinical assays, while newer moderate- and high-throughput assays offer the potential for rapid initial screening. Studies of radiation response modification by molecularly targeted agents can be improved using more physiologic 3D culture models. Elucidating effects on the cancer stem cells (CSC, and CSC-like) and developing biomarkers for defining targets and measuring responses are also important. In vivo studies are necessary to confirm in vitro findings, further define mechanism of action and address immune modulation and treatment-induced modification of the microenvironment. Newer in vivo models include genetically engineered and patient derived xenograft mouse models and spontaneously occurring cancers in domesticated animals. Selection of appropriate endpoints is important for in vivo studies, for example, regrowth delay measures bulk tumor killing while local tumor control assesses effects on CSC. The reliability of individual assays requires standardization of procedures and cross-laboratory validation. Radiation modifiers must be tested as part of clinical standard of care, which includes radio-chemotherapy for most tumors. Radiation models are compatible with, but also differ from those used for drug screening. Furthermore, the mechanism of a drug as a chemotherapy enhancer may be different than its interaction with radiation and/or radio-chemotherapy. This provides an opportunity to expand the use of molecular-targeted agents.

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“…Right panel, fraction of head and neck squamous cell cancer (HNSCC) cells with at least 20 γ-H2AX foci after treatment with IR with or without 17-AAG (Liu et al, unpublished). D) Radiosensitization factor for 2 Gy IR +/− 17-AAG using a previous IR/drug screening approach 129 . E) Representative images illustrating the persistence of 53BP1 foci following ex-vivo irradiation of tumor tissues from a bladder cancer patient.…”

Section: Figurementioning

confidence: 99%

DNA Damage Response Assessments in Human Tumor Samples Provide Functional Biomarkers of Radiosensitivity

Willers

Gheorghiu

Liu

et al. 2015

Seminars in Radiation Oncology

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Predictive biomarkers are urgently needed for individualization of radiation therapy and treatment with radiosensitizing anti-cancer agents. Genomic profiling of human cancers will provide us with unprecedented insight into the mutational landscape of genes directly or indirectly involved in the response to radiation-induced DNA damage. However, to what extent this wealth of structural information about the cancer genome will produce biomarkers of sensitivity to radiation remains to be seen. Investigators are increasingly studying the subnuclear accumulation (i.e., foci) of proteins in the DNA damage response (DDR), such as γ-H2AX, 53BP1, or RAD51, as a surrogate of treatment sensitivity. Recent findings from preclinical studies have demonstrated the predictive potential of DDR foci by correlating foci with clinically relevant endpoints such as tumor control probability. Therefore, pre-clinical investigations of DDR foci responses are increasingly moving into cells and tissues from patients, which is the major focus of this review. The advantage of using DDR foci as functional biomarkers is that they can detect alterations in DNA repair due to various mechanisms. Moreover, they provide a global measurement of DDR network function without needing to know the identities of all the components, many of which remain unknown. Foci assays are thus expected to yield functional insight that may complement or supersede genomic information, thereby giving radiation oncologists unique opportunities to individualize cancer treatments in the near future.

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Adapting a Drug Screening Platform to Discover Associations of Molecular Targeted Radiosensitizers with Genomic Biomarkers

Cited by 35 publications

References 45 publications

Radiation Resistance in KRAS-Mutated Lung Cancer Is Enabled by Stem-like Properties Mediated by an Osteopontin–EGFR Pathway

Radiation Resistance in KRAS-Mutated Lung Cancer Is Enabled by Stem-like Properties Mediated by an Osteopontin–EGFR Pathway

Improving the Predictive Value of Preclinical Studies in Support of Radiotherapy Clinical Trials

DNA Damage Response Assessments in Human Tumor Samples Provide Functional Biomarkers of Radiosensitivity

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