Calabuig-Fariñas, S. (Silvia)

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    Cancer epigenetic biomarkers in liquid biopsy for high incidence malignancies
    (2021) Palanca-Ballester, C. (Cora); Expósito, F. (Francisco); Jantus-Lewintre, E. (Eloisa); Calabuig-Fariñas, S. (Silvia); Rodríguez-Casanova, A. (Aitor); Montuenga-Badia, L.M. (Luis M.); Valencia, K. (Karmele); Redín, E. (Esther); Torres, S. (Susana); Serrano-Tejero, D. (Diego); Calvo-González, A. (Alfonso); Sandoval, J. (Juan); Diaz-Lagares, A. (Ángel)
    Simple Summary Apart from genetic changes, cancer is characterized by epigenetic alterations, which indicate modifications in the DNA (such as DNA methylation) and histones (such as methylation and acetylation), as well as gene expression regulation by non-coding (nc)RNAs. These changes can be used in biological fluids (liquid biopsies) for diagnosis, prognosis and prediction of cancer drug response. Although these alterations are not widely used as biomarkers in the clinical practice yet, increasing number of commercial kits and clinical trials are expected to prove that epigenetic changes are able to offer valuable information for cancer patients. Early alterations in cancer include the deregulation of epigenetic events such as changes in DNA methylation and abnormal levels of non-coding (nc)RNAs. Although these changes can be identified in tumors, alternative sources of samples may offer advantages over tissue biopsies. Because tumors shed DNA, RNA, and proteins, biological fluids containing these molecules can accurately reflect alterations found in cancer cells, not only coming from the primary tumor, but also from metastasis and from the tumor microenvironment (TME). Depending on the type of cancer, biological fluids encompass blood, urine, cerebrospinal fluid, and saliva, among others. Such samples are named with the general term "liquid biopsy" (LB).
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    Signature-driven repurposing of Midostaurin for combination with MEK1/2 and KRASG12C inhibitors in lung cancer
    (2023) Gil-Bazo, I. (Ignacio); Drosten, M. (Mathias); Barbacid, M. (Mariano); Kovalski, J. (Joanna); Pineda-Lucena, A. (Antonio); Román, M. (Marta); Jantus-Lewintre, E. (Eloisa); Calabuig-Fariñas, S. (Silvia); Vicent, S. (Silvestre); Ludwig, I.A. (Iziar Amaia); Entrialgo-Cadierno, R. (Rodrigo); Palomino-Echeverría, S. (Sara); Salmon, M. (Marina); Fernandez-Irigoyen, J. (Joaquín); Ruggero, D. (Davide); Lara-Astiaso, D. (David); Santos, A. (Alba); Ponz-Sarvise, M. (Mariano); Macaya, I. (Irati); Feliu, I. (Iker); Rodríguez-Remírez, M. (M.); Guruceaga, E. (Elizabeth); Paz-Ares, L. (Luis); Ferrer, I. (Irene); Narayanan, S. (Shruthi); Ferrero, M. (Macarena); Lecanda, F. (Fernando); Welch, C. (Connor); Lopez, I. (Inés); Lonfgren, S.M. (Shane M.); Santamaria, E. (Enrique); Khatri, P. (Purvesh)
    Drug combinations are key to circumvent resistance mechanisms compromising response to single anti-cancer targeted therapies. The implementation of combinatorial approaches involving MEK1/2 or KRASG12C inhibitors in the context of KRAS-mutated lung cancers focuses fundamentally on targeting KRAS proximal activators or effectors. However, the antitumor effect is highly determined by compensatory mechanisms arising in defined cell types or tumor subgroups. A potential strategy to find drug combinations targeting a larger fraction of KRAS-mutated lung cancers may capitalize on the common, distal gene expression output elicited by oncogenic KRAS. By integrating a signature-driven drug repurposing approach with a pairwise pharmacological screen, here we show synergistic drug combinations consisting of multi-tyrosine kinase PKC inhibitors together with MEK1/2 or KRASG12C inhibitors. Such combinations elicit a cytotoxic response in both in vitro and in vivo models, which in part involves inhibition of the PKC inhibitor target AURKB. Proteome profiling links dysregulation of MYC expression to the effect of both PKC inhibitor-based drug combinations. Furthermore, MYC overexpression appears as a resistance mechanism to MEK1/2 and KRASG12C inhibitors. Our study provides a rational framework for selecting drugs entering combinatorial strategies and unveils MEK1/2- and KRASG12C-based therapies for lung cancer.