Chemotherapy resistance mechanisms and targeted therapies in leukemia

Abstract

This thesis focuses on hematological malignancies, including leukemia. In contrast to solid tumors, leukemia cannot be surgically removed because it is spread throughout the body at diagnosis. Hence, it wasn’t until the advent of chemotherapy that hematological malignancies could be treated. Despite the advances in chemotherapeutic agents, the survival of patients with hematological malignancies remains poor. The main reason for this is chemotherapy resistance. While some causes of chemotherapy resistance have been identified, many mechanisms remain to be discovered. In this thesis, I have identified novel mechanisms that lead to chemotherapy resistance in leukemia. In addition, I discovered new targeted therapies to treat chemotherapy resistant disease. Firstly, I found that mutations in the epigenetic regulator SETD2 confer resistance to DNA damaging chemotherapy by abrogating the DNA damage response. Besides identifying a novel mechanism and mutation that causes chemotherapy resistance in leukemia, I identified a novel potential strategy to target these chemotherapy resistant, cells through inhibition of KDM4A or WEE1. Secondly, I demonstrate that PPM1D mutations confer chemotherapy resistance in leukemia, and show that PPM1D mutant cells selectively expand in the presence of chemotherapy. Not only does this finding provide us with a novel gene and mechanism of chemotherapy resistance in leukemia, it offers an explanation for the enrichment of PPM1D mutations in the blood of patients exposed to chemotherapy – where PPM1D mutations can be found in up to 25% of patients – and in therapy related hematological malignancies. We propose that the selective expansion of PPM1D mutant cells during chemotherapy treatment, similar to that seen for TP53 mutant cells, increases the risk of a therapy related malignancy later in life. Finally, we demonstrate that treatment with an allosteric, small molecule inhibitor of PPM1D preferentially kills PPM1D-mutant cells and reverses the chemoresistance phenotype of PPM1D mutant cells. These findings provide a novel targeted therapy for PPM1D mutant, chemotherapy resistant leukemia. In addition, given that the selective expansion of PPM1D mutations is likely to increase the risk of a therapy related malignancy, PPM1D inhibition may be used to prevent the development of a therapy related disease – hereby providing a preventative cancer therapy. Main conclusions - SETD2 mutations confer chemotherapy resistance in leukemia by an abrogation of the DNA damage response. KDM4a inhibition and/or WEE1 inhibitor therapy re-sensitize SETD2 mutant cells to chemotherapy, and can therefore be used as potential new targeted therapies in SETD2-mutant, chemotherapy resistant disease. Hence, these findings increase our understanding into the mechanisms of chemotherapy resistance in leukemia, and provide a novel therapeutic approach to treat chemotherapy resistant disease. - PPM1D mutations confer chemotherapy resistance and can be targeted with PPM1D inhibitor therapy. In addition, the presence of PPM1D mutations in the blood of people exposed to chemotherapy may increase the risk of therapy-related leukemia. The use of PPM1D inhibitors may therefore not only be used to treat chemotherapy resistant, PPM1D mutant leukemia, but may also be used to prevent the development of therapy related disease – hereby providing a novel therapeutic and preventative, cancer therapy. Main recommendations The presence of SETD2 or PPM1D mutations in patients with leukemia warrants the use of novel, non-chemotherapeutic treatment options, as these mutations confer resistance to chemotherapy. KDM4A inhibition or WEE1 inhibition can be used as a targeted therapy for SETD2 mutant leukemia, and a PPM1D inhibitor can be used to treat PPM1D mutant disease. In addition, the presence of PPM1D mutations in the blood cells of patients treated with chemotherapy is likely to increase the risk of a therapy related malignancy. The use of a PPM1D inhibitor in such patients prior to, or during chemotherapy exposure, may prevent the development of a therapy-related leukemia.