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  • American Association for Cancer Research (AACR)  (11)
  • 1
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    Online Resource
    Abstract 3454: Establishing role of KRAS mutation on NSCLC radio-sensitivity
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 8_Supplement ( 2012-04-15), p. 3454-3454
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 3454-3454
    Abstract: Lung cancer is the leading cause of cancer related mortality in the US of which more than 75% cases are that of non-small cell lung carcinoma (NSCLC). Mutations in the proto-oncogene KRAS have been linked with poor prognosis for NSCLC patients. In this study, we aimed at analyzing the relationship between specific KRAS mutations and NSCLC cell radiosensitivity and protein expression patterns. We analyzed 22 NSCLC cell lines and stratified them according to their KRAS status. Our results show that NSCLC cells harbouring G12C mutations are more sensitive to radiation compared to cells with other KRAS status (SF2 = 0.35 ± 0.16 for G12C vs. 0.63 ± 0.17 for other KRAS mutants vs 0.54 ± 0.15 for wt KRAS). Our protein expression data suggests that G12C mutants have reduced expression of DNA-repair proteins such as ATM, Rad 50, Ku 80 and XRCC1 (p & lt; 0.05) which may be responsible for their radiosensitive nature. Further we found that G12C mutant NSCLC cell lines have reduced expression of pAkt compared to cells with other KRAS status (p =0.009). This suggests that NSCLC cells harboring G12C mutation would be less susceptible to PI3K inhibition induced radio-sensitization. Our clonogenic assay results confirm our finding when 1-hour pretreatment with 5 µM LY294002 (PI3K inhibitor) sensitized H460 and A549 (non-G12C mutated NSCLC cells) but not H1792 and H23 (G12C mutant NSCLC). Our results strongly suggests that G12C KRAS mutant cells are radio-sensitive compared to NSCLC cells of other KRAS status and PI3K inhibitor therapy along with radiation could be beneficial for patients harboring non-G12C mutational KRAS status. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3454. doi:1538-7445.AM2012-3454
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2012-3454
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 2
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    Integrative Analysis of Head and Neck Cancer Identifies Two Biologically Distinct HPV and Three Non-HPV Subtypes
    American Association for Cancer Research (AACR) ; 2015
    In:  Clinical Cancer Research Vol. 21, No. 4 ( 2015-02-15), p. 870-881
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 21, No. 4 ( 2015-02-15), p. 870-881
    Abstract: Purpose: Current classification of head and neck squamous cell carcinomas (HNSCC) based on anatomic site and stage fails to capture biologic heterogeneity or adequately inform treatment. Experimental Design: Here, we use gene expression-based consensus clustering, copy number profiling, and human papillomavirus (HPV) status on a clinically homogenous cohort of 134 locoregionally advanced HNSCCs with 44% HPV+ tumors together with additional cohorts, which in total comprise 938 tumors, to identify HNSCC subtypes and discover several subtype-specific, translationally relevant characteristics. Results: We identified five subtypes of HNSCC, including two biologically distinct HPV subtypes. One HPV+ and one HPV− subtype show a prominent immune and mesenchymal phenotype. Prominent tumor infiltration with CD8+ lymphocytes characterizes this inflamed/mesenchymal subtype, independent of HPV status. Compared with other subtypes, the two HPV subtypes show low expression and no copy number events for EGFR/HER ligands. In contrast, the basal subtype is uniquely characterized by a prominent EGFR/HER signaling phenotype, negative HPV-status, as well as strong hypoxic differentiation not seen in other subtypes. Conclusion: Our five-subtype classification provides a comprehensive overview of HPV+ as well as HPV− HNSCC biology with significant translational implications for biomarker development and personalized care for patients with HNSCC. Clin Cancer Res; 21(4); 870–81. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-14-2481
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 3
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    Inhibition of Pulmonary and Skeletal Metastasis by a Transforming Growth Factor-β Type I Receptor Kinase Inhibitor
    American Association for Cancer Research (AACR) ; 2006
    In:  Cancer Research Vol. 66, No. 13 ( 2006-07-01), p. 6714-6721
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 66, No. 13 ( 2006-07-01), p. 6714-6721
    Abstract: Transforming growth factor-β (TGF-β) signaling has been shown to promote invasion and metastasis in various models of human cancers. In this study, we investigated the efficacy of a TGF-β type I receptor kinase inhibitor (TβRI-I) to limit early systemic metastases in an orthotopic xenograft model of lung metastasis and in an intracardiac injection model of experimental bone and lung metastasis using human breast carcinoma MDA-MB-435-F-L cells, a highly metastatic variant of human breast cancer MDA-MB-435 cells, expressing the enhanced green fluorescent protein (EGFP). Treatment of the cells with the TβRI-I had no effect on their growth but blocked TGF-β-stimulated expression of integrin αvβ3 and cell migration in vitro. Systemic administration of the TβRI-I via i.p. injection effectively reduced the number and size of the lung metastasis in both orthotopic xenograft and experimental metastasis models with no effects on primary tumor growth rate compared with controls. TβRI-I treatment also reduced the incidence of widespread early skeletal metastases in the femur, tibia, mandible, and spine detected by whole-body EGFP fluorescence imaging. Tumor burden in femora and tibiae was also reduced after TβRI-I treatment as detected by histomorphometry analysis compared with the placebo controls. Our results indicate for the first time that abrogation of TGF-β signaling by systemic administration of the TβRI-I can inhibit both early lung and bone metastasis in animal model systems and suggest antimetastatic therapeutic potential of the TβRI-I.(Cancer Res 2006; 66(13): 6714-21)
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-05-3565
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2006
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  • 4
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    Non–Small Cell Lung Cancers with Kinase Domain Mutations in the Epidermal Growth Factor Receptor Are Sensitive to Ionizing Radiation
    American Association for Cancer Research (AACR) ; 2006
    In:  Cancer Research Vol. 66, No. 19 ( 2006-10-01), p. 9601-9608
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 66, No. 19 ( 2006-10-01), p. 9601-9608
    Abstract: Non–small cell lung cancers (NSCLCs) bearing mutations in the tyrosine kinase domain (TKD) of the epidermal growth factor receptor (EGFR) often exhibit dramatic sensitivity to the EGFR tyrosine kinase inhibitors gefitinib and erlotinib. Ionizing radiation (IR) is frequently used in the treatment of NSCLC, but little is known how lung tumor–acquired EGFR mutations affect responses to IR. Because this is of great clinical importance, we investigated and found that clonogenic survival of mutant EGFR NSCLCs in response to IR was reduced 500- to 1,000-fold compared with wild-type (WT) EGFR NSCLCs. Exogenous expression of either the L858R point mutant or the ΔE746-E750 deletion mutant form of EGFR in immortalized human bronchial epithelial cells, p53 WT NSCLC (A549), or p53-null NSCLC (NCI-H1299) resulted in dramatically increased sensitivity to IR. We show that the majority of mutant EGFR NSCLCs, including those that contain the secondary gefitinib resistance T790M mutation, exhibit characteristics consistent with a radiosensitive phenotype, which include delayed DNA repair kinetics, defective IR-induced arrest in DNA synthesis or mitosis, and pronounced increases in apoptosis or micronuclei. Thus, understanding how activating mutations in the TKD domain of EGFR contribute to radiosensitivity should provide new insight into effective treatment of NSCLC with radiotherapy and perhaps avoid emergence of single agent drug resistance. (Cancer Res 2006; 66(19): 9601-07)
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-06-2627
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2006
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  • 5
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    DNA Repair Biomarker Profiling of Head and Neck Cancer: Ku80 Expression Predicts Locoregional Failure and Death following Radiotherapy
    American Association for Cancer Research (AACR) ; 2011
    In:  Clinical Cancer Research Vol. 17, No. 7 ( 2011-04-01), p. 2035-2043
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 17, No. 7 ( 2011-04-01), p. 2035-2043
    Abstract: Purpose: Radiotherapy plays an integral role in the treatment of head and neck squamous cell carcinoma (HNSCC). Although proteins involved in DNA repair may predict HNSCC response to radiotherapy, none has been validated in this context. We examined whether differential expression of double-strand DNA break (DSB) repair proteins in HNSCC, the chief mediators of DNA repair following irradiation, predict for treatment outcomes. Experimental Design: Archival HNSCC tumor specimens (n = 89) were assembled onto a tissue microarray and stained with antibodies raised against 38 biomarkers. The biomarker set was enriched for proteins involved in DSB repair, in addition to established mechanistic markers of radioresistance. Staining was correlated with treatment response and survival alongside established clinical and pathologic covariates. Results were validated in an independent intramural cohort (n = 34). Results: Ku80, a key mediator of DSB repair, correlated most closely with clinical outcomes. Ku80 was overexpressed in half of all tumors, and its expression was independent of all other covariates examined. Ku80 overexpression was an independent predictor for both locoregional failure and mortality following radiotherapy (P & lt; 0.01). The predictive power of Ku80 overexpression was confined largely to HPV-negative HNSCC, where it conferred a nine-fold greater risk of death at two years. Conclusions: Ku80 overexpression is a common feature of HNSCC, and is a candidate DNA repair-related biomarker for radiation treatment failure and death, particularly in patients with high-risk HPV-negative disease. It is a promising, mechanistically rational biomarker to select individual HPV-negative HNSCC patients for strategies to intensify treatment. Clin Cancer Res; 17(7); 2035–43. ©2011 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-10-2641
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 6
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    Somatic Mutations in the Tyrosine Kinase Domain of Epidermal Growth Factor Receptor (EGFR) Abrogate EGFR-Mediated Radioprotection in Non–Small Cell Lung Carcinoma
    American Association for Cancer Research (AACR) ; 2007
    In:  Cancer Research Vol. 67, No. 11 ( 2007-06-01), p. 5267-5274
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 67, No. 11 ( 2007-06-01), p. 5267-5274
    Abstract: The epidermal growth factor receptor (EGFR) is an important determinant of radioresponse, whose elevated expression and activity frequently correlates with radioresistance in several cancers, including non–small cell lung carcinoma (NSCLC). We reported recently that NSCLC cell lines harboring somatic, activating mutations in the tyrosine kinase domain (TKD) of the EGFR exhibit significant delays in the repair of DNA double-strand breaks (DSB) and poor clonogenic survival in response to radiation. Here, we explore the mechanisms underlying mutant EGFR-associated radiosensitivity. In three representative NSCLC cell lines, we show that, unlike wild-type (WT) EGFR, receptors with common oncogenic TKD mutations, L858R or ΔE746-E750, are defective in radiation-induced translocation to the nucleus and fail to bind the catalytic and regulatory subunits of the DNA-dependent protein kinase (DNA-PK), a key enzyme in the nonhomologous end-joining repair pathway. Moreover, despite the presence of WT EGFR, stable exogenous expression of either the L858R or the ΔE746-E750 mutant forms of EGFR in human bronchial epithelial cells significantly delays repair of ionizing radiation (IR)–induced DSBs, blocks the resolution of frank or microhomologous DNA ends, and abrogates IR-induced nuclear EGFR translocation or binding to DNA-PK catalytic subunit. Our study has identified a subset of naturally occurring EGFR mutations that lack a critical radioprotective function of EGFR, providing valuable insights on how the EGFR mediates cell survival in response to radiation in NSCLC cell lines. [Cancer Res 2007;67(11):5267–74]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-07-0242
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2007
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  • 7
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    Radiation-Induced DNA Damage Cooperates with Heterozygosity of TP53 and PTEN to Generate High-Grade Gliomas
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 14 ( 2019-07-15), p. 3749-3761
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 14 ( 2019-07-15), p. 3749-3761
    Abstract: Glioblastomas are lethal brain tumors that are treated with conventional radiation (X-rays and gamma rays) or particle radiation (protons and carbon ions). Paradoxically, radiation is also a risk factor for GBM development, raising the possibility that radiotherapy of brain tumors could promote tumor recurrence or trigger secondary gliomas. In this study, we determined whether tumor suppressor losses commonly displayed by patients with GBM confer susceptibility to radiation-induced glioma. Mice with Nestin-Cre-driven deletions of Trp53 and Pten alleles were intracranially irradiated with X-rays or charged particles of increasing atomic number and linear energy transfer (LET). Mice with loss of one allele each of Trp53 and Pten did not develop spontaneous gliomas, but were highly susceptible to radiation-induced gliomagenesis. Tumor development frequency after exposure to high-LET particle radiation was significantly higher compared with X-rays, in accordance with the irreparability of DNA double-strand breaks (DSB) induced by high-LET radiation. All resultant gliomas, regardless of radiation quality, presented histopathologic features of grade IV lesions and harbored populations of cancer stem-like cells with tumor-propagating properties. Furthermore, all tumors displayed concomitant loss of heterozygosity of Trp53 and Pten along with frequent amplification of the Met receptor tyrosine kinase, which conferred a stem cell phenotype to tumor cells. Our results demonstrate that radiation-induced DSBs cooperate with preexisting tumor suppressor losses to generate high-grade gliomas. Moreover, our mouse model can be used for studies on radiation-induced development of GBM and therapeutic strategies. Significance: This study uncovers mechanisms by which ionizing radiation, especially particle radiation, promote GBM development or recurrence.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-19-0680
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 8
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    Abstract 3272: Tumor treating fields combined with the PULSAR paradigm for radiotherapy and an immune checkpoint inhibitor enhances antitumor efficacy in vivo
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 3272-3272
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 3272-3272
    Abstract: Tumor Treating Fields (TTFields) is a new mode of physical cancer treatment that delivers low-intensity, intermediate frequency, alternating electric fields to tumors in a non-invasive manner. A number of in vitro studies have demonstrated that TTFields play an important role in suppressing the DNA damage pathways and increasing replication stress, in addition to interfering with mitosis. During interphase TTFields creates a conditional vulnerability environment that would make cells more susceptible to radiation and chemotherapy. The PULSAR concept relies on ablative doses of radiation spaced at least one week apart to allow a tumor to adapt to the first radiation dose before a second dose of radiation is applied. As a result, the therapy should be less toxic and be adaptable according to changes in tumor morphology, location, and response to radiation. TTFields seems well suited to the PULSAR paradigm given the time between radiation doses where TTFields application would have the potential to enhance tumor response to a subsequent radiation exposure and this is described here. First, in in vitro studies, a greater increase in radiation susceptibility was observed when cells were exposed to TTFields before radiation (IR) treatment compared to IR treatment followed by TTFields. In the present study, TTFields were combined with IR or IR+immune checkpoint inhibitor (ICI) to evaluate the combinatorial effectiveness in mouse tumor models. Three syngeneic mouse tumor models, LLC (Murine Lewis Lung Carcinoma), KPC63 (Pancreatic Cancer) and MC38 (Colon Cancer), were used in the initial tumor growth delay (TGD) studies. TTFields exposure increased TGD in all three mouse models, but the difference in tumor volume over time was not statistically significant due to small sample sizes. Combination studies were then initiated using the MC38 mouse model since TTFields resulted in a greater TGD effect in this model. The first in vivo experiment combined one round of TTFields with radiation therapy, which significantly delayed tumor growth. The combined efficacy of two rounds of TTFields and IR treatment was further delayed compared to radiation or TTFields alone. The combination of TTFields prior to each IR dose, two rounds of IR spaced one week apart, and an ICI (PD-L1 Ab) given sequentially inhibited tumor growth far more than either TTFields plus the ICI or TTFields plus IR or IR plus the ICI alone. To explain this increased efficacy immune-related changes in the tumor microenvironment is being evaluated. In addition, gene expression analysis is also ongoing to confirm the changes in gene expression underlying the in vitro TTFields effect on DNA repair and replication stress. In conclusion, the PULSAR paradigm for radiotherapy seems well suited for the application of TTFields prior to each radiation dose and that effect is enhanced when an ICI is also introduced. Citation Format: Narasimha K. Karanam, Zengfu Shang, Robert Timmerman, Michael D. Story, Debabrata Saha. Tumor treating fields combined with the PULSAR paradigm for radiotherapy and an immune checkpoint inhibitor enhances antitumor efficacy in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3272.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-3272
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 9
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    Abstract LB-88: Gene expression signatures predictive of clinical outcome and tumor mutations in refractory NSCLC patients (pts) in the BATTLE trial (Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination)
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. LB-88-LB-88
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. LB-88-LB-88
    Abstract: Background: There are currently no established markers to identify pts bearing wild-type EGFR who are likely to benefit from erlotinib (ERLO). The EGFR and Kras pathways, and epithelial to mesenchymal transition (EMT), have been associated with response/resistance to EGFR inhibitors. We developed gene signatures for these pathways and tested whether they were predictive of disease control (DC) and tumor mutations using gene expression profiles from pts in the BATTLE trial, and developed novel markers for ERLO benefit in wt EGFR pts. Methods: Gene expression profiles (Affymetrix HG1.0ST) from pretreatment core needle biopsies (CNBs) were obtained from 101 BATTLE pts. Pathways signatures were developed using independent datasets from resected NSCLC pts and cell lines. A robust EGFR mutation signature was derived by comparing genes differentially expressed in mutated and wt EGFR lung adenocarcinoma from 3 independent institutions, and validated in three independent sets, both in vivo and in vitro. A KRAS signature was similarly derived. An EMT signature was derived by identifying genes with a bimodal distribution and correlated with known EMT genes (E-cadherin, vimentin, N-cadherin, FN-1) using 54 NSCLC cell lines, and validated in an independent panel of HN cell lines and across different platforms. A novel 5-gene signature was derived using erlotinib-treated BATTLE patients with or without 8 week DC, the primary study endpoint. Results: The EGFR and Kras signatures predicted EGFR and Kras mutations, respectively, in BATTLE patients (AUC 0.72 by ROC analysis, p=0.03 for EGFR; AUC 0.67, p=0.0.01 for KRas signature). In pts with wt EGFR and Kras, the EMT and 5-gene, but not the EGFR or KRas signatures, were associated with improved DC in ERLO treated pts (EMT signature: 64% for epithelial vs 10% mesenchymal groups, p=0.02; 5-gene: 83% vs 0%, p= & lt;.001) and progression-free survival (PFS). The EGFR, EMT and 5-gene signatures were also significantly associated with in vitro sensitivity to ERLO in NSCLC cell lines. LCN2/NGAL, part of the 5-gene signature, was found to be associated with the epithelial phenotype. Potential therapeutic targets associated with mesenchymal phenotype including Axl were identified by the EMT signature. Conclusions: Gene expression profiling from CNBs is a feasible approach for predicting response and identifying activated oncogenic pathways and potential therapeutic targets in refractory NSCLC pts. EGFR and Kras signatures predicted mutation status but, in wt EGFR patients, did not predict efficacy. EMT and a novel 5-gene signature including LCN2/NGAL were predictive of DC in pts with wt EGFR treated in BATTLE and merit further investigation as markers of benefit for EGFR inhibitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-88. doi:10.1158/1538-7445.AM2011-LB-88
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-LB-88
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 10
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    Abstract 3441: Proteomic profiling identifies PTK2/FAK as a targetable marker of radioresistance in head and neck cancer
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 3441-3441
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 3441-3441
    Abstract: One of the primary treatments for head and neck squamous cell carcinoma (HNSCC) is radiotherapy. Despite decades of study, few if any targetable biomarkers for resistance to this modality. To systematically evaluate resistance to radiotherapy in HNSCC, we evaluated 50 HNSCC cell lines using reverse phase protein array (RPPA). Utilizing this method we identified 11 protein markers with altered expression in radioresistant HNSCC cell lines (FDR 1%), including PTK2/FAK. Both PTK2/Fak gene expression and copy number were highly correlated to PTK2/Fak protein expression and both were associated with radioresistance in these cell lines. Additionally, in clinical samples from the TCGA, PTK2/Fak copy number was highly associated with gene expression, with high expression levels in HNSCC tumors. To validate the association between PTK2/Fak and clinical radioresistance in HNSCC, we examined PTK2/FAK copy number in two separate cohorts of HNSCC patients treated uniformly with radiotherapy (n = 39 and n = 44). In both cohorts, PTK2/Fak amplification was associated with treatment failure following radiotherapy (p = 0.04 and p = 0.03 respectively and p = 0.004 for the combined population). Additionally, in a separate cohort of HNSCC patients treated with radiotherapy, high levels of PTK2/Fak gene expression were associated with failure following radiotherapy (p = 0.02). Additionally, in vitro pharmacologic inhibition of PTK2/FAK function led to radiosensitization in multiple HNSCC cell lines, primarily via induction of G2/M arrest, with minimal apoptosis observed. Taken together, these data identify a validated, targetable biomarker of radioresistance in HNSCC. Citation Format: Heath D. Skinner, Uma Giri, John S. Yordy, Michael D. Story, Jing Wang, Lauren A. Byers, Michelle D. Williams, Adel K. El-Naggar, Sang H. Woo, Liang P. Yang, You Fan, Curtis R. Pickering, Jeffrey N. Myers,, John V. Heymach. Proteomic profiling identifies PTK2/FAK as a targetable marker of radioresistance in head and neck cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3441. doi:10.1158/1538-7445.AM2015-3441
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-3441
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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