Improving cancer therapy through unraveling drug resistance

Abstract

The discovery that the growth and/or survival of cancer cells is dependent on certain oncogenic drivers — also described as ‘oncogene addiction’ — provided a rationale for the development of targeted agents that specifically inhibit aberrant oncoproteins. Unfortunately, the initial expectation that precision medicine would revolutionize cancer treatment turned out to be overly optimistic. The success of targeted cancer therapies is hampered by (1) a lack of predictive biomarkers, (2) the rapid development of therapy resistance, and (3) a paucity of suitable drug targets. The work described in this thesis aimed to provide insights that address these problems. In chapter 2 we describe how resistance to PIM kinase inhibitors in acute myeloid leukemia (AML) occurs through p38α-mediated feedback activation of mTOR signaling. We provide a rationale for combining PIM and p38 inhibitors to overcome therapy resistance. In chapter 3 we identify PIM kinases as a potential therapeutic target and prognostic biomarker in neuroblastoma. We furthermore demonstrate that NF1 loss mediates resistance to PIM kinase inhibitors and is a potential predictive biomarker for PIM inhibitor therapy. In chapter 4 we identify FGFR1 as a potential prognostic biomarker in head and neck squamous cell carcinoma (HNSCC). We suggest that FGFR inhibitors might be useful for the treatment of HNSCC — either as monotherapy or in combination with an EGFR inhibitor for FGFR inhibitor-resistant HNSCC. In chapter 5 we discuss the role of TGF-β signaling as a drug resistance mechanism to both targeted and conventional therapies. We demonstrate that elevated TGF-β signaling is associated with a poor prognosis subtype in colorectal cancer and that TGF-β might induce chemotherapy resistance by suppressing apoptosis. In chapter 6 I discuss the challenges that need to be overcome to improve the benefit of targeted therapies.