Raf kinase inhibitor protein (RKIP) as a novel predictor of molecular targeted therapies response in solid tumors

Raf kinase inhibitor protein (RKIP), was first described as an inhibitor of MAPK pathway, which accounts for its current name. However, subsequent studies have shown that RKIP is involved in other intracellular signaling pathways. Thus, RKIP downregulation is associated with prognosis and malignant progression in several tumor types, as demonstrated by our and other groups. Moreover, the downregulation of RKIP led to tumor cells being resistant to conventional chemotherapy. Due to the important role of RKIP in the regulation of important intracellular signaling pathways, and its involvement in tumor microenvironment modulation, we believe that RKIP can also modulate tumor cells response to oncogene-targeted therapies. Thus, the major aim of this project is to shed light on the mechanisms of cancer cells response to oncogene targeted therapies, by studying the role of RKIP expression in the modulation of tumors response to established oncogene targeted therapies, including immunotherapy, in solid tumors.

Funding Agency

LPCC FCT PhD Fellowships

Project Reference

LPCC	LPCC-NRN SCHOLARSHIP 2020
FCT PhD Fellowships	SFRH/BD/141200/2018 SFRH/BD/148199/2019 2021/07647/BD 2021/08171/BD

Project Members

Olga Martinho

Affiliated Researcher Project Leader

Rui M. Reis

Principal Investigator

Sara Granja

Affiliated Researcher

Ana Raquel-Cunha

PhD Student

Diana Cardoso-Carneiro

PhD Student

Joana Pinheiro

PhD Student

Patrícia Fontão

PhD Student

Main Project Outcomes

Cardoso-Carneiro D, Raquel-Cunha A, Pinheiro J, Gabriela-Freitas M, Fontão P, Reis RM, Martinho O. Implications of RKIP protein in cancer prognosis and therapy response: a literature update. In “Prognostic and Therapeutic Applications of RKIP in Cancer”, Chapter 20, Bonavida B. & Baritaki S., Elsevier. 2020. Pages 389-414

Gabriela-Freitas M, Pinheiro J, Raquel-Cunha A, Cardoso-Carneiro D, Martinho O. RKIP as an Inflammatory and Immune System Modulator: Implications in Cancer. Biomolecules 2019, 9, 769.

Raquel-Cunha A, Cardoso-Carneiro D, Reis RM, Martinho O. Current Status of Raf Kinase Inhibitor Protein (RKIP) in Lung Cancer: behind RTK signaling. Cells 2019, 8(5), 442.

Martinho O, Campos M, Ribeiro G, Penna V, Curcelli EC, Olivieri MV, Morini S, Scapulatempo C, Abrahão-Machado LF, Reis RM. Raf kinase inhibitor protein (RKIP) expression and prognostic value in soft tissue sarcomas. Pathobiology. 2016;83(1):41-6.

Martinho O, Pinto F, Granja S, Miranda-Gonçalves V, Moreira MA, Ribeiro LF, di Loreto C, Rosner MR, Longatto-Filho A, Reis RM. RKIP inhibition in cervical cancer is associated with higher tumor aggressive behavior and resistance to cisplatin therapy. PLoS One. 2013;8(3):e59104.

Martinho O, Simões K, Longatto-Filho A, Jacob CE, Zilberstein B, Bresciani C, Gama-Rodrigues J, Cecconello I, Alves V, Reis RM. “Absence of RKIP expression is an independent prognostic biomarker in gastric cancer”. Oncol Rep. 2013 Feb;29(2):690-6.

Martinho O, Granja S, Jaraquemada T, Caeiro C, Miranda-Gonçalves V, Honavar M, Costa P, Damasceno M, Rosner MR, Lopes JM, Reis RM. Downregulation of RKIP is associated with poor outcome and malignant progression in gliomas. PLoS ONE 2012 7(1): e30769.

Martinho O, Faloppa CC, Neto CS, Longatto-Filho A, Baiocchi G, da Cunha IW, Soares FA, Fregnani JH, Reis RM. Loss of RKIP expression during the carcinogenic evolution of endometrial cancer. J Clin Pathol. 2012 Feb;65(2):122-8.

Martinho O, Gouveia A, Silva P, Pimenta A, Reis RM, Lopes JM. Loss of RKIP expression is associated with poor survival in GISTs. Virchows Archiv, 2009, 455(3):277-84.

Maria Gabriela Freitas, Master in Health Sciences, University of Minho, 2018-2020; Title: “Oncogenic interplay between RKIP and PD-L1 in lung cancer: implications to immunotherapy response.”

Joana Pinheiro, Master in Health Sciences, University of Minho,2018-2020; Title: “Role of RKIP protein in the modulation of cancer cell metabolism in solid tumors.”

Ana Raquel Cunha, Master in Health Sciences, University of Minho, 2017-2019; Title: “Exploiting RKIP protein as a novel predictor of EGFR targeted therapies response in lung cancer.”

Inês Lages, Master in Health Sciences, University of Minho, 2017-2019; Title: “Dissecting chemotherapy resistance in prostate cancer: Interplay between RKIP and Brachyury proteins.”

Diana Carneiro, Master in Health Sciences, University of Minho, 2016-2017; Title: “Raf kinase inhibitor protein (RKIP) as a modulator of oncogene targeted therapies response in Cervical Cancer”.

Olga Martinho: RKIP as a modulator of oncogene targeted therapy response in solid tumors. 2nd International Symposium on Prognostic and Therapeutic Implications of RKIP in Cancer. 9–10th May 2019, Heraklion, Crete, Greece.

Olga Martinho: Raf Kinase Inhibitory Protein (RKIP): a new predictor of EGFR targeted therapy response in solid tumors? VII International Symposium on Translational Oncology, 13 to 14 September 2019, Hospital de Câncer de Barretos, Brazil.

Olga Martinho: RTKs Molecular Targeted therapy: a new hope for cervical cancer. Conferences on Oncobiology 2018 of the Faculty of Pharmacy of the University of Porto, under the theme “New Therapeutic Approaches”. 15 May 2018, Porto, Portugal.

Olga Martinho: Implications of RKIP Protein in Cancer Prognosis and Therapy Response. Seminary at “Unidade de Investigação em Patobiologia Molecular (UIPM) do Instituto Português de Oncologia de Lisboa Francisco Gentil EPE”, 12 December 2019, Lisbon, Portugal.

Olga Martinho is a Member of the “Raf Kinase Inhibitory Protein Consortium” (https://www.rkip.info/members-1 )