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Redig, Amanda J

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Redig

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Amanda J

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Redig, Amanda J
Author's Publications: search.filters.isAuthorOfPublication.ac66ec20-3512-4ffb-8190-6be7b076dbe0

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    Targeting BET bromodomain proteins in solid tumors
    (Impact Journals LLC, 2016) Sahai, Vaibhav; Redig, Amanda J; Collier, Katharine A.; Eckerdt, Frank D.; Munshi, Hidayatullah G.
    There is increasing interest in inhibitors targeting BET (bromodomain and extra-terminal) proteins because of the association between this family of proteins and cancer progression. BET inhibitors were initially shown to have efficacy in hematologic malignancies; however, a number of studies have now shown that BET inhibitors can also block progression of non-hematologic malignancies. In this Review, we summarize the efficacy of BET inhibitors in select solid tumors; evaluate the role of BET proteins in mediating resistance to current targeted therapies; and consider potential toxicities of BET inhibitors. We also evaluate recently characterized mechanisms of resistance to BET inhibitors; summarize ongoing clinical trials with these inhibitors; and discuss potential future roles of BET inhibitors in patients with solid tumors.
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    Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2
    (Nature Publishing Group, 2017) Zhang, Haikuo; Fillmore Brainson, Christine; Koyama, Shohei; Redig, Amanda J; Chen, Ting; Li, Shuai; Gupta, Manav; Garcia-de-Alba, Carolina; Paschini, Margherita; Herter-Sprie, Grit S.; Lu, Gang; Zhang, Xin; Marsh, Bryan P.; Tuminello, Stephanie J.; Xu, Chunxiao; Chen, Zhao; Wang, Xiaoen; Akbay, Esra A.; Zheng, Mei; Palakurthi, Sangeetha; Sholl, Lynette; Rustgi, Anil K.; Kwiatkowski, David; Diehl, J Alan; Bass, Adam; Sharpless, Norman E.; Dranoff, Glenn; Hammerman, Peter S.; Ji, Hongbin; Bardeesy, Nabeel; Saur, Dieter; Watanabe, Hideo; Kim, Carla; Wong, Kwok-Kin
    Adenosquamous lung tumours, which are extremely poor prognosis, may result from cellular plasticity. Here, we demonstrate lineage switching of KRAS+ lung adenocarcinomas (ADC) to squamous cell carcinoma (SCC) through deletion of Lkb1 (Stk11) in autochthonous and transplant models. Chromatin analysis reveals loss of H3K27me3 and gain of H3K27ac and H3K4me3 at squamous lineage genes, including Sox2, ΔNp63 and Ngfr. SCC lesions have higher levels of the H3K27 methyltransferase EZH2 than the ADC lesions, but there is a clear lack of the essential Polycomb Repressive Complex 2 (PRC2) subunit EED in the SCC lesions. The pattern of high EZH2, but low H3K27me3 mark, is also prevalent in human lung SCC and SCC regions within ADSCC tumours. Using FACS-isolated populations, we demonstrate that bronchioalveolar stem cells and club cells are the likely cells-of-origin for SCC transitioned tumours. These findings shed light on the epigenetics and cellular origins of lineage-specific lung tumours.
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    KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer
    (eLife Sciences Publications, Ltd, 2017) Krall, Elsa B; Wang, Belinda; Munoz, Diana M; Ilic, Nina; Raghavan, Srivatsan; Niederst, Matthew J; Yu, Kristine; Ruddy, David A; Aguirre, Andrew; Kim, Jong Wook; Redig, Amanda J; Gainor, Justin; Williams, Juliet A; Asara, John; Doench, John G; Janne, Pasi; Shaw, Alice; McDonald III, Robert E; Engelman, Jeffrey A; Stegmeier, Frank; Schlabach, Michael R; Hahn, William
    Inhibitors that target the receptor tyrosine kinase (RTK)/Ras/mitogen-activated protein kinase (MAPK) pathway have led to clinical responses in lung and other cancers, but some patients fail to respond and in those that do resistance inevitably occurs (Balak et al., 2006; Kosaka et al., 2006; Rudin et al., 2013; Wagle et al., 2011). To understand intrinsic and acquired resistance to inhibition of MAPK signaling, we performed CRISPR-Cas9 gene deletion screens in the setting of BRAF, MEK, EGFR, and ALK inhibition. Loss of KEAP1, a negative regulator of NFE2L2/NRF2, modulated the response to BRAF, MEK, EGFR, and ALK inhibition in BRAF-, NRAS-, KRAS-, EGFR-, and ALK-mutant lung cancer cells. Treatment with inhibitors targeting the RTK/MAPK pathway increased reactive oxygen species (ROS) in cells with intact KEAP1, and loss of KEAP1 abrogated this increase. In addition, loss of KEAP1 altered cell metabolism to allow cells to proliferate in the absence of MAPK signaling. These observations suggest that alterations in the KEAP1/NRF2 pathway may promote survival in the presence of multiple inhibitors targeting the RTK/Ras/MAPK pathway. DOI: http://dx.doi.org/10.7554/eLife.18970.001