PP01.32 Proteasome Hyperactivity as a Targetable Vulnerability in Oncogenic Missense TP53 Mutated NSCLC

Abstract

Despite advances in targeted approaches and immunotherapy, 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 strategies for patients with non-small cell lung cancer (NSCLC). Gain-of-function (GOF) oncogenic TP53 mutations, which are present in 20-30% of NSCLC, are harbingers of poorer prognosis and subdued responses to therapy. To date, strategies aimed at directly targeting mutant p53 have not been successful. Here, we provide evidence of proteasome hyperactivity in GOF mutant p53 NSCLC and show that this could be a targetable vulnerability specific to this subset of NSCLC.