Lung cancer (LC) is the leading cause of cancer related death in the USA and in the world. Activating
mutations of the proto-oncogene KRAS (mutant KRAS, KM thereafter) occur in ~30% of non-small cell lung
cancer (NSCLC). These cancers are associated with an aggressive phenotype, resistance to therapy and poor
outcome. Expression of KM in the respiratory epithelium is sufficient to initiate lung tumorigenesis.
Furthermore, KM is required for the maintenance of established tumors. These observations establish KM as
a high priority drug target. Only a minority of patients with KM-driven LC benefit from therapy, including
immunotherapy or KRASG12C inhibitors. Accordingly, patients with KMLC have a poor prognosis. Hence,
there is an urgent need for effective therapies for KMLC.
Cancer cells undergo oncogene-directed metabolic reprogramming in order to meet the energetic and
biosynthetic challenges of cell survival, growth and proliferation. It has been proposed that these changes are
critical for the maintenance of established cancers. Indeed, we found that extinction of KM in LC of transgenic
mice leads to the perturbation of several metabolic networks including fatty acid (FA) synthesis.
To determine the contribution of lipid metabolism to KM-driven LC, we characterized the lipidome of KMLC
with high resolution mass spectrometry, matrix-assisted laser desorption/ionization imaging MS (MALDI-IMS) and
functional experiments. Our preliminary data indicate that KM upregulates Fatty acid synthase (FASN) and
the synthesis of FA to repair peroxided phospholipids (PL) damaged by reactive oxygen species (ROS).
FASN is often upregulated in cancer, however its role has remained elusive. We found that inhibition of
FASN with TVB-3664, a first in class FASN inhibitor (FASNi), induces ferroptosis, a form of iron- and ROS-
dependent programmed cell death characterized by the accumulation of lipid peroxides both in vitro and in vivo in
preclinical models of KMLC. Lipidomics analysis and functional experiments suppressing ACSL3, LPCAT3 and
PLA2G4C strongly suggest that in KMLC, FA serve a prosurvival function by feeding the Lands cycle, the main
process that remodels the peroxided acyl chains of PL, deflecting ferroptosis.
These observations support the hypothesis that KMLC depends on FA to evade ferroptosis and to
promote tumorigenesis. We propose to test this hypothesis with a multifaceted approach that employs KM
transgenic mice, panels of LC cells lines, functional and lipidomics experiments. it is worth noting that our
group provided the rationale for a phase II clinical trial of TVB-2640, a FASNi derivative, in patients with
KMLC (NCI identifier NCT03808558). We anticipate that these studies will contribute to a better understanding
of cellular metabolic networks required for KM driven tumorigenesis, providing the framework for the development
of novel cancer therapies.