The role of MAPK 38 in resistance of breast cancer and osteolytic bone metastases to inhibitors of the mevalonate pathway

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The mevalonate pathway is an essential signaling pathway that can be blocked by bisphosphonates and statins. While bisphosphonates inhibit bone-resorbing osteoclasts, statins are used to lower the synthesis of cholesterol. Numerous studies describe direct and indirect anti-tumor effects by both drugs. However, high concentrations, which likely exceed those attainable in clinical practice, are required to obtain significant effects. In the first funding period, we demonstrated that sequential blockade of the mevalonate pathway using statins and zoledronic acid significantly lowers the concentrations of these drugs needed to achieve effective anti-tumor effects in human breast cancer cells. In addition, a significant suppression of DKK-1 was observed using this approach. DKK-1 is an inhibitor of osteoblastic differentiation and has emerged as a key modulator of osteolytic bone metastases. However, the treatment with statins and zoledronic acid activated the mitogen activated protein kinase (MAPK) p38, and pharmacological inhibition of p38 enhanced the induction of apoptosis by atorvastatin in breast cancer cells. Furthermore, a direct regulation of DKK-1 by p38 was demonstrated in human cancer cells.Based on these findings we hypothesize that activation of p38 results in a breast cancer cell resistance to the anti-tumor activities of mevalonate pathway inhibitors. Thus, we consider the blockade of p38 as a promising approach to sensitize human breast cancer cells to the anti-tumor and DKK-1 suppressive effects of statins and zoledronic acid. To test this hypothesis, we first aim to comprehensively characterize the anti-tumor effects mediated by the simultaneous inhibition of p38 and the mevalonate pathway. Specifically, we intend to identify the respective isoforms of p38 that are responsible for the observed resistance. Our findings will be confirmed by using appropriate animal models of both primary tumor growth and osteolytic bone metastases. Here, p38 will be knocked down using RNA interference or pharmacological inhibitors in the tumor cells, and mice will be treated with statins and zoledronic acid after tumor cell inoculation. Thus, we will assess if and how the reduced expression of DKK-1 in the tumor cells might potentially reduce the occurrence of osteolytic lesions in bone metastases. To underline the significance of our findings, primary breast cancer tissue will be analyzed to determine a link between the mevalonate pathway activity with the expression of DKK-1 and p38. Our study aims to identify an important resistance mechanism of breast cancer cells against inhibitors of the mevalonate pathway that might contribute to ineffective anti-tumor effects observed with clinical doses of statins and zoledronic acid.