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The p38MAPK signaling pathway was initially described as a stress response mechanism. In fact, during previous decades, it was considered a pathway with little interest in oncology especially in comparison with other MAPKs such as ERK1/2, known to be target of oncogenes like Ras. However, its involvement in apoptotic cell death phenomena makes this signaling pathway more attractive for many cancer research laboratories. This apoptotic role allows to establish a link between p38MAPK and regular chemotherapeutic agents such as Cisplatin or base analogs (Cytarabine, Gemcitabine or 5-Fluorouracil) which are currently used in hospitals across the world. In fact, and more recently, p38MAPK has also been connected with targeted therapies like tyrosine kinase inhibitors (vg. Imatinib, Sorafenib) and, to a lesser extent, with monoclonal antibodies. In addition, the oncogenic or tumor suppressor potential of this signaling pathway has aroused the interest of the scientific community in evaluating p38MAPK as a novel target for cancer therapy. In this review, we will summarize the role of p38MAPK in chemotherapy as well as the potential that p38MAPK inhibition can bring to cancer therapy. All the evidences suggest that p38MAPK could be a double-edged sword and that the search for the most appropriate candidate patients, depending on their pathology and treatment, will lead to a more rational use of this new therapeutic tool.

Resistance to cisplatin is a major challenge in the current cancer therapy. In order to explore new therapeutic strategies to cisplatin resistance, we evaluated, in a model of lung cancer (H1299 and H460 cell lines), the nature of the pathways leading to cell death. We observed that H1299 displayed a natural resistance to cisplatin due to an inability to trigger an apoptotic response that correlates with the induction of autophagy. However, pharmacological and genetic approaches showed how autophagy was a mechanism associated to cell death rather than to resistance. Indeed, pro-autophagic stimuli such as mTOR or Akt inhibition mediate cell death in both cell lines to a similar extent. We next evaluated the response to a novel platinum compound, monoplatin, able to promote cell death in an exclusive autophagy-dependent manner. In this case, no differences were observed between both cell lines. Furthermore, in response to monoplatin, two molecular hallmarks of cisplatin response (p53 and MAPKs) were not implicated, indicating the ability of this pro-autophagic compound to overcome cisplatin resistance. In summary, our data highlight how induction of autophagy could be used in cisplatin resistant tumours and an alternative treatment for p53 mutated patient in a synthetic lethally approach.

ObjectivesTo fully clarify the role of Mitogen Activated Protein Kinase in the therapeutic response to Sorafenib in Renal Cell Carcinoma as well as the cell death mechanism associated to this kinase inhibitor, we have evaluated the implication of several Mitogen Activated Protein Kinases in Renal Cell Carcinoma-derived cell lines.Materials and methodsAn experimental model of Renal Cell Carcinoma-derived cell lines (ACHN and 786-O cells) was evaluated in terms of viability by MTT assay, induction of apoptosis by caspase 3/7 activity, autophagy induction by LC3 lipidation, and p62 degradation and kinase activity using phospho-targeted antibodies. Knock down of ATG5 and ERK5 was performed using lentiviral vector coding specific shRNAResultsOur data discard Extracellular Regulated Kinase 1/2 and 5 as well as p38 Mitogen Activated Protein Kinase pathways as mediators of Sorafenib toxic effect but instead indicate that the inhibitory effect is exerted through the PI3K/Akt signalling pathway. Furthermore, we demonstrate that inhibition of Akt mediates cell death associated to Sorafenib without caspase activation, and this is consistent with the induction of autophagy, as indicated by the use of pharmacological and genetic approaches.ConclusionThe present report demonstrates that Sorafenib exerts its toxic effect through the induction of autophagy in an Akt-dependent fashion without the implication of Mitogen Activated Protein Kinase. Therefore, our data discard the use of inhibitors of the RAF-MEK-ERK1/2 signalling pathway in RCC and support the use of pro-autophagic compounds, opening new therapeutic opportunities for Renal Cell Carcinoma.

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