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Exploring IKKbeta kinase as a therapeutic target for lung tumour-initiating cells induced by the KRAS oncogene

Grant number: 16/22520-4
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): June 01, 2017
Effective date (End): August 31, 2018
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Acordo de Cooperação: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:Daniela Sanchez Basseres
Grantee:Felipe Silva Rodrigues
Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated scholarship(s):17/22125-0 - Investigating the role of IKKbeta kinase and ERBB in the maintenance of the cancer stem-like phenotype in KRAS-driven lung cancer, BE.EP.MS


Lung cancer induced by oncogenic mutations of the KRAS GTPase is a very frequent disease, for which there are currently no effective therapies. Although these mutations are closely linked to oncogenesis, different approaches to inhibit RAS proteins directly have previously failed. Therefore, for better therapeutic targets for lung cancer to become available, it is necessary to identify the downstream pathways activated by KRAS, which are directly involved in the acquisition of important malignant properties. One of the most significant characteristics of malignant behavior is the acquisition of a cancer stem-like phenotype by tumour-initiating cells (TIC). TICs are defined as a subpopulation of self-renewing tumor cells able to initiate tumor formation and sustain tumour growth. They are also resistant to chemo- and radiotherapy and it is believed that they are responsible for tumour recurrence and metastatic dissemination. The development of new therapeutic approaches targeting these cells is essential for improving the efficacy of current antitumour therapies. Since KRAS is associated with the expansion and maintenance of a cancer stem cell phenotype, the aim of this project is to identify new therapeutic targets that contribute to the KRAS-induced cancer stem-like phenotype in the lung epithelium. We postulate that (1) IKKbeta kinase promotes the cancer stem-like phenotype; and that (2) targeting IKKbeta in KRAS-positive lung cell lines will reduce the number of TICs. This hypothesis was formulated on the basis of recent studies indicating that pharmacological inhibition of IKKbeta reduces the number of mammary and prostate TICs, and that pharmacological inhibition of IKKbeta activity in an animal model of KRAS-induced lung cancer decreased tumour growth, as well as prevented tumour progression to more advanced histological grades. To test these hypotheses we will use pharmacological and genetic approaches to inhibit IKKbeta, and assess how IKKbeta inhibition affects the number of TICs, the expression of cancer stem cell markers and the ability of purified TICs to form tumourspheres and to selfrenew in vitro. The rationale that drives this research project is that it is expected to elucidate the molecular mechanisms involved in the KRAS-induced maintenance and expansion of lung TICs, which are, in turn, important for tumour recurrence and metastatic spread. It is also expected that this project will contribute to the development of new therapeutic strategies for KRAS-induced lung cancer, as well as other KRAS-induced malignancies. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
RODRIGUES, FELIPE SILVA; MIRANDA, VANESSA SILVA; CARNEIRO-LOBO, TATIANA CORREA; SCALABRINI, LUIZA COIMBRA; KRUSPIG, BJORN; LEVANTINI, ELENA; MURPHY, DANIEL J.; BASSERES, DANIELA SANCHEZ. IKK beta Kinase Promotes Stemness, Migration, and Invasion in KRAS-Driven Lung Adenocarcinoma Cells. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 21, n. 16, . (16/10404-0, 16/22520-4, 12/13774-1, 16/19757-2, 17/22125-0)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
RODRIGUES, Felipe Silva. Exploring IKKb kinase as a therapeutic target for KRAS-driven lung tumour-initiating cells. 2018. Master's Dissertation - Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ) São Paulo.

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