The hunt for a new guardian of the genome

Abstract

For more than a century, tumor treatment has relied on genotoxic therapies that exploit the inherent sensitivity of cancer cells to DNA damage. The discovery of X-rays and the subsequent development of radiotherapy at the end of the 19th century proved highly effective in shrinking tumors, an achievement that helped catalyze early research into cancer biology. Chemotherapy was developed in the mid-20th century and represented the first treatment modality capable of effectively addressing metastatic cancer. The advancement of these genotoxic treatments led to substantial improvements in patient survival; for example, the five-year survival rate for patients with acute myeloid leukemia and non-Hodgkin lymphoma (NHL) has risen from nearly zero to over 75% since 1950. Radiotherapy and chemotherapy function by inducing DNA damage, to which cancer cells are hypersensitive due to their rapid proliferation, genetic defects, and high levels of cellular stress. However, these same vulnerabilities also exert selection pressure, favoring chemotherapy-resistant clones and contributing to treatment failure. Despite a century of progress in genotoxic therapies, the majority of patients with metastatic cancer still succumb to the disease because their metastases develop resistance to all available chemotherapies through a process known as multidrug resistance. The fact that cancer can develop resistance to chemotherapy was described as early as the first publication on chemotherapy in NHL patients. Nevertheless, after more than fifty years of research, no universal mechanism explaining chemotherapy resistance has been identified. One of the most extensively studied processes regarding chemotherapy sensitivity is apoptosis. Cells undergo apoptosis, or programmed cell death, in response to cellular stress. The tumor suppressor protein p53 is crucial in this process, as it stimulates the transcription of pro-apoptotic proteins and thus triggers apoptosis in response to DNA damage. Consequently, the loss of p53 is essential for tumorigenesis, earning p53 the moniker "guardian of the genome." The ability of cancer cells to evade p53-dependent apoptosis is therefore considered one of the "hallmarks of cancer." Initially, this led to the hypothesis that p53 would also be a critical factor in chemotherapy resistance. However, the idea that p53-dependent apoptosis is central to chemotherapy sensitivity was subsequently abandoned as the clinical relevance of p53 proved to be limited. Remarkably, p53-independent apoptosis following DNA damage remains poorly characterized, despite it being known for decades that p53-deficient cells can undergo apoptosis in response to chemotherapy in various contexts. Most studies offer only a partial explanation, or none at all, for how p53-independent apoptosis occurs. Prior to our research, an overarching mechanism describing the execution of p53-independent apoptosis in response to DNA damage had not been established. This led to our central research question: how does p53-independent apoptosis occur in response to chemotherapy? In this thesis, we describe the elucidation and characterization of a novel, general DNA damage response in which Schlafen11 (SLFN11) induces ribosome stagnation, followed by p53-independent apoptosis.