Regulation of the Mdm2/p53 tumor suppressor network in drug response and resistance

The tumor suppressor p53 is one of the most frequently lost or mutated genes in human cancer. As a transcription factor, p53 responds to cellular stress by inducing target genes that promote cell cycle arrest, DNA repair, apoptosis, or senescence. Because p53 plays a central role in determining cell fate decisions, elucidating the signaling circuitry that governs p53 function is critical for understanding tumorigenesis and manipulating p53 for therapeutic purposes.

Our recent findings have uncovered a novel mechanism of p53 regulation that impacts the cellular response to DNA damage. We discovered that the Caspase-2-PIDDosome complex is responsible for cleavage and inhibition of Mdm2, a master regulator of p53, during the DNA damage response. Our goal is to determine the role of Mdm2 cleavage in p53 signaling and therapeutic resistance. These studies will contribute to our understanding of drug resistance mechanisms as well as p53 pathway regulation in normal development and cancer. Specifically, our primary research objectives are:

1. Testing whether inhibition of the Caspase-2-PIDDosome sensitizes lung tumors to chemotherapy in vivo
2. Interrogating the biological role of Mdm2 cleavage in development, tumorigenesis, and chemotherapy response
3. Determining whether the p53-induced Caspase-2-PIDDosome positive feedback loop alters the pulsatile dynamics of p53 signaling or the functional outcome of p53 activity

Identifying drug resistance mechanisms in different subtypes of lung cancer

Our previous work focused on cisplatin resistance mechanisms in lung adenocarcinomas, a common subtype of non-small cell lung cancer (NSCLC). The other major type of lung cancer, small cell lung cancer (SCLC), is initially highly responsive to chemotherapy but frequently acquires vicious resistance. It is unknown why this pattern of response differs from NSCLC.

The tumor cell of origin and/or underlying genetic lesions may play a critical role in determining response. Mouse models of SCLC have been created based on conditional genetic loss of the tumor suppressors Rb and p53. We seek to use genomic and gene expression analyses to identify and compare chemotherapy resistance mechanisms in mouse models of SCLC and NSCLC. Understanding how the genetic characteristics of a given tumor dictate therapeutic response will help tailor therapy to the individual.