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Exploring IKKbeta as an anti-metastatic therapeutic target in KRAS-induced lung câncer

Grant number: 16/10404-0
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): August 01, 2016
Effective date (End): July 31, 2018
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal Investigator:Daniela Sanchez Basseres
Grantee:Vanessa Silva Miranda
Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil


Lung cancer is the leading cause of cancer deaths worldwide. The most frequent genetic changes found in lung cancer are driver mutations in the KRAS proto-oncogene. Even though KRAS mutations have been causally linked to the oncogenic process, therapies targeted to oncogenic RAS have failed in clinical trials. Therefore, in order to select better targets for lung cancer therapy, it will be necessary to identify KRAS downstream pathways involved in the establishment of critical oncogenic characteristics. One of the main characteristics in oncogenesis is the ability of tumors to acquire metastatic capability. The objective of this project is to identify therapeutic targets that reduce KRAS-induced lung cancer metastasis. Based on previous reports that oncogenic KRAS, drives not only tumor initiation, but also promotes a metastatic phenotype, the hypothesis of this project is that (1) the acquisition of metastatic ability induced by KRAS in the lung is potentiated by the IKKbeta kinase; and (2) that IKKbeta inhibition will reduce KRAS-induced cell invasive properties and KRAS-induced tumor metastasis. This hypothesis has been formulated on the basis of previous studies showing that the main IKKbeta substrate, the transcription factor NF-kappaB, is activated by KRAS in lung tumors in situ in an IKKbeta-dependent manner, that NF-kappaB is known to promote metastasis in different tumor models, and that pharmacological IKKbeta inhibition in a KRAS-induced lung cancer mouse model reduces tumor growth and progression to higher histological tumor grades. The rationale that governs this proposal is that we expect to elucidate the molecular mechanism involved in KRAS-mediated acquisition of invasive and metastatic properties. In addition, we expect to validate new strategies to develop anti-tumor therapies.

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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)
MIRANDA, Vanessa Silva. Exploring IKKβ as an anti-metastatic therapeutic target in KRAS-induced lung câncer. 2019. Master's Dissertation - Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ) São Paulo.

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