| Summary: | The discovery of functionally relevant KRAS effectors in lung and
PDAC may yield novel molecular targets or mechanisms amenable to inhibition
strategies. Here, we studied the role of PITPNC1 and its controlled network in
the development and progression of both mutant KRAS-driven cancers.
Genetic modulation of KRAS expression as well as pharmacological
inhibition of canonical effectors was done. PITPNC1 genetic depletion was
performed in in vitro and in vivo LUAD and PDAC models. PITPNC1-deficient
cells were RNA sequenced, and Gene Ontology and enrichment analyses
applied to the output data. Protein-based biochemical and subcellular
localization assays were run to investigate PITPNC1-regulated pathways. A
drug repurposing approach was used to predict surrogate PITPNC1 inhibitors
that were tested in combination with KRASG12C inhibitors in 2D, 3D and in vivo
models. PITPNC1 was increased in human LUAD and PDAC, and associated
with poor patients survival. PITPNC1 was regulated by KRAS through MEK1/2
and JNK1/2. Functional experiments showed PITPNC1 requirement for cell
proliferation, cell cycle progression and tumour growth. PITPNC1 controlled a
transcriptional signature that highly overlapped with a KRAS-regulated one.
Notably, PITPNC1 loss induced autophagy by decreasing MYC protein
expression and preventing mTOR localization to lysosomes. A JAK2 inhibitor
was predicted as putative PITPNC1 inhibitor and also induced autophagy and
displayed antiproliferative effect. Furthermore, its combination with a
KRASG12C inhibitor elicited a substantial antitumor effect in LUAD and PDAC.
Our data highlight the functional and clinical relevance of
PITPNC1 in LUAD and PDAC. Moreover, PITPNC1 constitutes a new
mechanism that regulates the KRAS downstream targets MYC and mTOR, and
controls a druggable transcriptional network for combinatorial treatments.
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