Investigating p16 Loss in Pro-tumorigenic Metabolism

Project Summary/Abstract
The ultimate goal of this proposal is to address a fundamental gap in knowledge on the role of the cell cycle
inhibitor p16 in regulating pro-tumorigenic metabolism. The results from these studies could have a significant
impact on the treatment of melanoma patients, of which ~30-40% have downregulation or deletion of p16. This
research plan focuses on experimentally and mechanistically determining the role of p16 loss in pro-tumorigenic
nucleotide metabolism and whether this pathway can be targeted in p16-low melanomas alone or in combination
with mutant BRAF inhibitors to obtain a sustained therapeutic response. The proposed studies are based on
preliminary findings that loss of p16 expression upregulates the newly-identified ATR-mTORC1 signaling axis to
increase nucleotide metabolism through the pentose phosphate pathway, and modulation of this pathway is a
metabolic vulnerability for p16-low cancer cells. In line with these data, we will explore two overarching scientific
aims: 1) to mechanistically dissect the ATR-mTORC1 pathway downstream of p16 loss in melanomagenesis
and determine the contribution of pro-tumorigenic nucleotide metabolism to the observed phenotypes; and 2) to
elucidate whether targeting the ATR-mTORC1 pathway in combination is synergistic in p16-low melanomas
alone or in combination with mutant BRAF inhibitors. The completion of the scientific aims of this proposal will
not only provide new mechanistic insights into the interplay between metabolism and the cell cycle during
tumorigenesis, but will also establish targeting the novel ATR-mTORC1 axis as a strategy to improve therapeutic
outcome for melanoma patients with low p16 expression. The proposed research is of high impact because the
mechanistic underpinning of these pathways has the potential to transform the management of melanomas with
low p16. As p16 is altered in ~50% of all human cancers, these studies will have far-reaching implications for
identifying metabolic vulnerabilities and developing future cancer therapeutic strategies for a wide range of
patients.

Grant Number: 4R37CA240625-06
NIH Institute/Center: NIH
Principal Investigator: Katherine Aird