RESUMO
Exploiting oxidative stress has recently emerged as a plausible strategy for treatment of human cancer, and antioxidant defenses are implicated in resistance to chemotherapy and radiotherapy. Targeted suppression of antioxidant defenses could thus broadly improve therapeutic outcomes. Here, we identify the AMPK-related kinase NUAK1 as a key component of the antioxidant stress response pathway and reveal a specific requirement for this role of NUAK1 in colorectal cancer. We show that NUAK1 is activated by oxidative stress and that this activation is required to facilitate nuclear import of the antioxidant master regulator NRF2: Activation of NUAK1 coordinates PP1ß inhibition with AKT activation in order to suppress GSK3ß-dependent inhibition of NRF2 nuclear import. Deletion of NUAK1 suppresses formation of colorectal tumors, whereas acute depletion of NUAK1 induces regression of preexisting autochthonous tumors. Importantly, elevated expression of NUAK1 in human colorectal cancer is associated with more aggressive disease and reduced overall survival.Significance: This work identifies NUAK1 as a key facilitator of the adaptive antioxidant response that is associated with aggressive disease and worse outcome in human colorectal cancer. Our data suggest that transient NUAK1 inhibition may provide a safe and effective means for treatment of human colorectal cancer via disruption of intrinsic antioxidant defenses. Cancer Discov; 8(5); 632-47. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 517.
Assuntos
Neoplasias Colorretais/metabolismo , Estresse Oxidativo , Proteínas Quinases/metabolismo , Proteínas Repressoras/metabolismo , Animais , Sítios de Ligação , Biomarcadores , Pólipos do Colo/genética , Pólipos do Colo/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Progressão da Doença , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Linfonodos/patologia , Camundongos , Modelos Biológicos , Fator 2 Relacionado a NF-E2/metabolismo , Motivos de Nucleotídeos , Prognóstico , Ligação Proteica , Proteínas Quinases/genética , Transporte Proteico , Espécies Reativas de Oxigênio/metabolismo , Proteínas Repressoras/genéticaRESUMO
BACKGROUND: Oncotype DX (ODX), a tumor gene profiling test, has been incorporated into clinical guidelines to aid in adjuvant chemotherapy decision making for early-stage, hormone receptor positive breast cancer patients. Despite United States (U.S.) guidelines, less than half of eligible women receive testing. Reasons for low usage are unclear: Our objective was to better understand U.S. oncologists' ODX uptake and how they use ODX during adjuvant chemotherapy decision making. METHODS: We conducted semi-structured, ~30-minute phone interviews with medical and surgical oncologists in one U.S. State using purposive sampling. Oncologists were included if they saw greater than or equal to five breast cancer patients per week. Recruitment ended upon thematic saturation. Interviews were recorded, transcribed, and double-coded using template analysis. RESULTS: During analysis, themes emerged across three domains. First, organizational factors (i.e., departmental structure, ODX marketing, and medical/insurance guidelines) influenced ease of ODX use. Second, oncologists referenced the influence of interpersonal factors (e.g., normative beliefs and peer use of ODX) over their own practices and recommendations. Third, intrapersonal factors (e.g., oncologist attitudes, perceived barriers, and research gaps) were discussed: although oncologists largely held positive attitudes about ODX, they reported challenges with interpreting intermediate scores for treatment decisions and explaining test results to patients. Finally, oncologists identified several research gaps. CONCLUSIONS: As more tumor gene profiling tests are incorporated into cancer care for treatment decision making, it is important to understand their use in clinical practice. This study identified multi-level factors that influence ODX uptake into clinical practice, providing insights into facilitators and modifiable barriers that can be leveraged for improving ODX uptake to aid treatment decision making.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Quimioterapia Adjuvante/estatística & dados numéricos , Perfilação da Expressão Gênica/estatística & dados numéricos , Oncologistas/estatística & dados numéricos , Adulto , Biomarcadores Tumorais , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Entrevistas como Assunto , Masculino , Pessoa de Meia-Idade , Medicina de Precisão , Pesquisa QualitativaRESUMO
Oncotype DX testing (ODX), a tumor gene expression test, may improve breast cancer care, however, communicating results remains challenging. We identified patient-centered communication strategies/gaps for discussing ODX results. We applied a patient-centered communication framework to analyze qualitative interviews with oncologists about how they communicate about ODX with patients, using template analysis in Atlas.ti. Overall, providers discussed four patient-centered communication domains: exchanging information, assessing uncertainty, making decisions and cross-cutting themes. Providers did not report discussing emotional aspects of managing uncertainty, assessing decision-making preferences, and evaluating decisions. A patient-centered approach may be a model for communicating about tumor gene expression tests.
