López-López, R. (Rafael)

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20192

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    Identification of novel synthetic lethal vulnerability in non small cell lung cancer by co targeting TMPRSS4 and DDR1
    (Springer Science and Business Media LLC, 2019) Pajares, M.J. (María José); Expósito, F. (Francisco); Pio, R. (Rubén); Sainz, C. (Cristina); Jantus-Lewintre, E. (Eloisa); Camps, C. (Carlos); Montuenga-Badia, L.M. (Luis M.); Villalba-Esparza, M. (María); Guruceaga, E. (Elizabeth); López-López, R. (Rafael); Redrado, M. (Miriam); Valencia, K. (Karmele); Redín, E. (Esther); Lahoz, A. (Agustín); Andrea, C.E. (Carlos Eduardo) de; Calvo-González, A. (Alfonso); Sandoval, J. (Juan); Cirauqui, C. (Cristina); Hervas, D. (D.); Diaz-Lagares, A. (Ángel)
    Finding novel targets in non-small cell lung cancer (NSCLC) is highly needed and identification of synthetic lethality between two genes is a new approach to target NSCLC. We previously found that TMPRSS4 promotes NSCLC growth and constitutes a prognostic biomarker. Here, through large-scale analyses across 5 public databases we identified consistent co-expression between TMPRSS4 and DDR1. Similar to TMPRSS4, DDR1 promoter was hypomethylated in NSCLC in 3 independent cohorts and hypomethylation was an independent prognostic factor of disease-free survival. Treatment with 5-azacitidine increased DDR1 levels in cell lines, suggesting an epigenetic regulation. Cells lacking TMPRSS4 were highly sensitive to the cytotoxic effect of the DDR1 inhibitor dasatinib. TMPRSS4/DDR1 double knock-down (KD) cells, but not single KD cells suffered a G0/G1 cell cycle arrest with loss of E2F1 and cyclins A and B, increased p21 levels and a larger number of cells in apoptosis. Moreover, double KD cells were highly sensitized to cisplatin, which caused massive apoptosis (~40%). In vivo studies demonstrated tumor regression in double KD-injected mice. In conclusion, we have identified a novel vulnerability in NSCLC resulting from a synthetic lethal interaction between DDR1 and TMPRSS4.
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    Combination of KIR2DS4 and FcγRIIa polymorphisms predicts the response to cetuximab in KRAS mutant metastatic colorectal cancer
    (Nature Publishing Group, 2019) Hernandez, I. (I.); Cervantes, A. (Andrés); Rodríguez, J. (J.); Puime-Otin, A. (A.); Valladares, M. (M.); Vega-Bravo, R. (R.); Cebrián, A. (A.); Borrero-Palacios, A. (A.); Garcia-Alfonso, P. (P.); Vieitez, J.M. (J. M.); Rodríguez-Remírez, M. (M.); Garcia-Foncillas, J. (Jesús); López-López, R. (Rafael); García-Carbonero, R. (R.); Martinez-Useros, J. (Javier); García, J.L. (J. L.); Nadal, C. (C.); Guillén-Ponce, C. (C.); Rincón, R. (R.); Rojo-Todo, F. (Federico); Elez, E. (E.); Puerto-Nevado, L. (L.) del; Aranda, E. (E.)
    Cetuximab is a standard-of-care treatment for RAS wild-type metastatic colorectal cancer (mCRC) but not for those harbor a KRAS mutation since MAPK pathway is constitutively activated. Nevertheless, cetuximab also exerts its effect by its immunomodulatory activity despite the presence of RAS mutation. The aim of this study was to determine the impact of polymorphism FcγRIIIa V158F and killer immunoglobulin-like receptor (KIR) genes on the outcome of mCRC patients with KRAS mutations treated with cetuximab. This multicenter Phase II clinical trial included 70 mCRC patients with KRAS mutated. We found KIR2DS4 gene was significantly associated with OS (HR 2.27; 95% CI, 1.08-4.77; P = 0.03). In non-functional receptor homozygotes the median OS was 2.6 months longer than in carriers of one copy of full receptor. Multivariate analysis confirmed KIR2DS4 as a favorable prognostic marker for OS (HR 6.71) in mCRC patients with KRAS mutation treated with cetuximab. These data support the potential therapeutic of cetuximab in KRAS mutated mCRC carrying non-functional receptor KIR2DS4 since these patients significantly prolong their OS even after heavily treatment. KIR2DS4 typing could be used as predictive marker for identifying RAS mutated patients that could benefit from combination approaches of anti-EGFR monoclonal antibodies and other immunotherapies to overcome the resistance mediated by mutation in RAS.