Therapeutic Targeting of Oncogenic Gain-of-Function Mutant p53 by Proteasome Inhibition

Abstract

Non-small cell lung cancer (NSCLC) is a molecularly complex and heterogenous disease. Recent advances in genomic profiling have changed the therapeutic landscape of NSCLC to incorporate targeted and immunotherapeutic approaches. Despite these advances, lung cancer remains the leading cause of cancer mortality in the United States and worldwide. This is partly because these novel treatments are not applicable to all patients and are often associated with primary or secondary resistance. This highlights the need for continued search for new therapeutic agents and strategies for NSCLC patients.

However, the drug discovery and development pipeline is protracted and inherently expensive for new drugs. The projected timeline from identification of a new drug candidate from preclinical research to clinical trials and approval is estimated at about 12-15 years with an average cost of $1.3 billion [1]. Moreover, the failure rate for new drugs during the clinical development stage is high, reaching up to 96% by some estimates [2] and is partly due to adverse risk profiles of candidate molecules. Given the ongoing need for continued drug development in lung cancer, repurposing previously approved drugs for new indications when possible is advantageous. Such strategies decrease the cost and timeframe of drug development and pose a lower safety risk to patients since the toxicity profiles of the repurposed drugs are already well established.

Drug repurposing has had success in cancer therapy. Some of these include the repositioning of thalidomide for use in multiple myeloma and the repurposing of rituximab from lymphoma to incorporate its use in rheumatoid arthritis [3]. Interestingly, the observations that led to many drug repurposing efforts were serendipitous by nature.

However, recently more systematic approaches to repurposing drugs are being employed and include retrospective clinical analysis, genetic associations and pathway matching, binding assays to identify relevant target interactions, and large-scale in vitro drug screens with paired genomic data [3].

In this thesis compilation, I first and foremost lay the groundwork for repurposing proteasome inhibitors for therapeutic targeting of gain-of-function (GOF) oncogenic mutant p53 using lung cancer as a model disease. This has a potential for generalizability across cancers that bear GOF p53 mutations since alterations in TP53 are central to carcinogenesis and prevalent across tumor types. As the ‘guardian of the genome’, p53 maintains the genome integrity by inducing DNA damage repair or forcing aberrant cells into apoptosis or senescence. Failure of this function results in propagation of abnormal cells and the progression from normal to precancerous and malignant cells. Moreover, gain-of-function (GOF) activities of mutated TP53 related the acquisition of novel oncogenic properties are well described in the literature and are related to excess accumulation of the mutant protein.

This work describes the mechanism of paradoxical destabilization of GOF p53 by proteasome inhibition in lung cancer and identifies ‘hyperactive’ proteasome genes in mutant p53 as targetable vulnerabilities in this subset of NSCLC. Since proteasome inhibitors are FDA approved drugs and prior drug candidates targeting p53 have not had success in clinical development, the final goal is to repurpose proteasome inhibitors to target GOF p53 mutant NSCLC.