Systematic analysis of the novel effectors PITPNC1 and HMGCS1 in mutant KRAS tumours
Materias Investigacion::Ciencias de la Salud::Oncología
Mutant KRAS tumours
Mutant KRAS cancers
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Universidad de Navarra
ENTRIALGO, Rodrigo. "Systematic analysis of the novel effectors PITPNC1 and HMGCS1 in mutant KRAS tumours". Vicent, S. (dir.). Tesis doctoral. Universidad de Navarra, Pamplona, 2022.
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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