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I. Garmendia



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    MA17 - Genetic Drivers (ID 409)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Biology/Pathology
    • Presentations: 1
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      MA17.10 - YES1 Kinase is a New Therapeutic Target in Non-small Cell Lung Cancer (ID 7159)

      14:20 - 15:50  |  Author(s): I. Garmendia

      • Abstract
      • Presentation
      • Slides

      Background:
      Next-generation sequencing techniques have allowed the discovery of driver mutations in non-small cell lung cancer (NSCLC) that can be translated into advances in cancer diagnosis and treatment. However, specific oncogenic alterations are still unknown in a high proportion of NSCLC patients, that therefore cannot benefit from targeted therapies. The challenge is to identify new genetic alterations that allow the use of molecular-targeted therapies. In previous studies from our group (Aramburu et al. BMC Genomics 2015), the analysis of tumor molecular profiles from patients with NSCLC allowed us to identify the DNA copy number amplification of YES1 kinase (v-YES-1 Yamaguchi sarcoma viral oncogene homolog 1) as a prognostic marker in lung cancer. YES1 kinase is member of the Src family of non-receptor protein tyrosine kinases that are involved in the regulation of cell growth, apoptosis, cell-cell adhesion, cytoskeleton remodeling, and differentiation. The aim of this project is to evaluate if YES1 is a driver gene in NSCLC, and if targeting its activation may be a potential new therapeutic strategy.

      Methods:
      We first evaluated the prognostic role of YES1 protein expression in two independent series of 76 and 234 NSCLC patients, respectively. In both series, the multivariate analysis revealed that high YES1 expression is an independent poor prognostic factor for overall survival (CUN series HR: 3.416 [0.933-12.508]; MD Anderson series HR: 1.570 [1.032-2.391]). We next evaluated the effect of YES1 knockdown in 5 NSCLC cell lines with YES1 amplification and overexpression, and in 3 cell lines without YES1 amplification and with low protein expression. YES1 downregulation by two specific siRNAs decreased proliferation and cell survival only in those cells overexpressing YES1. Congruently, YES1 inhibition led to apoptosis only in those cells.

      Results:
      Consistent with these results, constitutive overexpression of YES1 in cells with low YES1 expression significantly enhanced cell proliferation. We next evaluated the effect of the multitarget Src kinase inhibitor dasatinib on the proliferation of NSCLC cell lines with high (8 cell lines) or low (4 cell lines) YES1 expression. Dasatinib dramatically inhibited proliferation in high YES1-expressing cell lines, whereas low YES1 cell lines were more resistant to dasatinib treatment (GI50s were four orders of magnitude higher in resistant cells).

      Conclusion:
      In conclusion, our results indicate that YES1 is a promising therapeutic target in NSCLC. Furthermore, amplification and high expression of YES1 may define a subset of patients who may potentially benefit from dasatinib treatment.

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