PROJECT SUMMARY
Autophagy is an intracellular recycling process controlled by the kinase ULK1 that is important in the survival
and growth of KRAS mutant lung tumors. Our team and others have shown that nutrient-stressed non-small cell
lung cancer (NSCLC) cells are highly sensitive to ULK1 inhibition, which suggests that nutrient depletion caused
by tumor growth may create vulnerability to autophagy inhibition. Because the field lacks potent and selective
small-molecule inhibitors that target ULK1 in vivo, we have developed and published a potent and selective
ULK1 inhibitor, ULK-101. In this application, we propose preclinical studies to further develop ULK-101 as an
anti-cancer agent, and we will evaluate the compound both alone and in combination with molecularly-targeted
therapies. We hypothesize that ULK-101 will suppress autophagy through ULK1 inhibition and thereby reduce
KRAS-driven lung tumor growth and improve therapeutic efficacy. To test our hypothesis, we propose the
following aims:
Specific Aim #1: Determine the efficacy of a potent and selective ULK1 inhibitor on autophagy and tumor
burden in mutant KRAS-driven NSCLC. In Aim 1, we will establish the level of autophagy inhibition by ULK-
101 in engrafted lung tumor cells. These KRASG12C lung cancer xenograft models will be used to test the
hypothesis that ULK-101 treatment reduces tumor progression and that dual targeting of both KRAS and ULK1
will be an effective strategy for KRASG12C driven lung tumors.
Specific Aim #2: Establish the therapeutic potential of an ULK1 inhibitor in genetically engineered
NSCLC mouse models. In Aim 2, we will test whether the small molecule inhibitor ULK-101 will decrease tumor
burden as a single agent in a KrasLSL-G12D and KrasLSL-G12C mouse models of NSCLC. Further, we expect that
ULK-101 will enhance the sensitivity of tumors to clinically relevant therapies, including the first KRAS-targeted
drug (AMG-510), to show promise in clinical trials of NSCLC. The mouse models used here complement the
xenograft models by featuring mice with a functional immune system, tumors at the appropriate site, and disease
progression that parallels the progression of human lung cancer.
We will exploit a unique vulnerability in KRAS-driven tumors by inhibiting the autophagy pathway with a novel
molecularly targeted therapy, ULK-101. While directly targeting KRAS has historically proven challenging, there
has been a recent breakthrough with allele-specific inhibitors, prompted by promising early results in clinical trials
with AMG-510, a G12C-specific KRAS inhibitor. Ultimately, we hope that evaluating ULK-101 as a single agent
and in combination with other therapeutics like AMG-510, will provide essential data to serve as a foundation for
new and more effective treatments for lung cancer patients.