Synergistic interaction between the oral platinum analog satraplatin and erlotinib Free

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Satraplatin (JM216) is a novel platinum analog with good oral bioavailability. A randomized, double blind Phase III trial with the combination of satraplatin and prednisone as 2^nd line treatment for patients with hormone refractory prostate cancer is ongoing. Preliminary results from this trial show that satraplatin significantly reduced the risk of disease progression. In addition, various Phase II studies are investigating the clinical activity of satraplatin in several other cancers including non-small cell lung cancer (NSCLC). In preclinical studies, JM118 (the active metabolite of JM216) was active a number of different tumor models and in cells resistant to cisplatin, carboplatin and oxaliplatin. Erlotinib (Tarceva®) is a potent inhibitor of the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). Since upregulation of the Erk and p38 pathways, which are downstream of EGFR, may play a role in the resistance to platinum analogs, we evaluated whether inhibition of this pathway by erlotinib would enhance the sensitivity of NSCLC (A549, SW1573), colon (Lovo, WiDr) and ovarian (A2780, 2008) cancer cell lines to JM118. The interaction between JM118 and erlotinib was evaluated with the median drug effect analysis, in which a combination index (CI) <0.9 is considered synergistic, 0.9<CI<1.1 additive and >1.1 antagonistic. Cells were exposed to a fixed ratio of the drugs, based on the IC₅₀. At simultaneous exposure, JM118 and erlotinib were synergistic in A549 and Lovo cells (CI: 0.6, 0.8), and additive in the other cell lines. Pretreatment with JM118 resulted in synergism in all cell lines (CI: 0.5-0.9). Mechanistic studies focused on changes in the phosphorylation of Akt, Erk and p38. In A549 cells exposure for 2 hr at IC₅₀ to erlotinib, JM118 and the combination increased p-Akt; erlotinib and the combination also increased p-Erk. In the SW1573 cell line no modulation of p-Erk or p-Akt was observed. In Lovo cells p-Erk was increased with JM118 and the combination, JM118 increased p-Akt. In 2008 cells erlotinib increased both p-Erk and p-Akt, JM118 increased p-Akt and the combination increased p-Akt and p-Erk. In A2780 cells p-Akt was increased with erlotinib and the combination, while p-Erk was increased with all three treatments. These data indicate that the combination of JM118 and erlotinib interferes with p-Erk and p-Akt signaling downstream of EGFR, while p38 signaling was not modulated. Comparing these results to the effect of the combination, an increase in p-Erk is related to a synergistic effect and a decrease or no change in p-Erk is related to an additive or antagonistic effect. In conclusion, JM118 is synergistic with erlotinib in all cell lines, which may be related to changes in signaling, especially the p-Erk pathway. A randomized Phase II trial is currently investigating the clinical benefit of satraplatin and erlotinib, administered in a sequential schedule, for elderly patients with advanced NSCLC.