TARGETING CANCER METABOLISM WITH FASTING-MIMICKING DIET¿BASED LOW-TOXIC COMBINATION THERAPIES: OVERCOMING RESISTANCE THROUGH METABOLIC SYNERGY
type: CreativeWork
description: Aging represents the highest risk factor for cancer, defined by molecular hallmarks such as genomic instability, telomere attrition, deregulated nutrient sensing, and chronic inflammation promoting malignant transformation. Among age-associated cancers, non-small cell lung cancer (NSCLC) is the most prevalent and lethal, with KRAS mutations occurring in up to 25–30% of lung adenocarcinomas. Tumors harbouring this mutated oncogene are particularly resistant to targeted therapies, highlighting the need for novel targeted low-toxicity strategies. Nutrient restriction interventions, such as fasting and fasting-mimicking diets (FMD), modulate conserved growth pathways (IGF-1/AKT/mTOR, AMPK) and enhance cellular stress resistance, offering a promising approach to cancer therapy. FMD, if combined with treatments like pharmacological doses of ascorbate could effectively target NSCLC rewired metabolism that sustains NSCLC progression. In this thesis, I investigated the combinatorial effects of FMD and pharmacological doses of vitamin C in KRAS-mutant NSCLC. In vitro, short-term starvation (STS) synergized with vitamin C to induce dramatic cell death in KRAS-mutant and wild- type NSCLC cell lines, while protecting normal cells. In vivo, cycles of FMD combined with high-dose vitamin C significantly delayed tumor growth in both immunodeficient (NSG) and immunocompetent (C57BL/6) mouse models, without inducing major toxicity. However, as previously demonstrated in our studies, cancer cells resist FMD through upregulation of starvation escape pathways. Here, mechanistically, RNA sequencing (RNA-seq) analysis revealed that resistant subpopulations upregulated MAPK signaling as an acute adaptive response, while chronic exposure drove additional activation of PI3K-AKT pathways to resist FMD and vitamin C treatment. Pharmacological blockade of EGFR/ERK (Afatinib, Ulixertinib) or PI3K (Pictilisib), particularly in dual ERK/PI3K inhibition, synergized with FMD and vitamin C to overcome…
abstract: Aging represents the highest risk factor for cancer, defined by molecular hallmarks such as genomic instability, telomere attrition, deregulated nutrient sensing, and chronic inflammation promoting malignant transformation. Among age-associated cancers, non-small cell lung cancer (NSCLC) is the most prevalent and lethal, with KRAS mutations occurring in up to 25–30% of lung adenocarcinomas. Tumors harbouring this mutated oncogene are particularly resistant to targeted therapies, highlighting the need for novel targeted low-toxicity strategies. Nutrient restriction interventions, such as fasting and fasting-mimicking diets (FMD), modulate conserved growth pathways (IGF-1/AKT/mTOR, AMPK) and enhance cellular stress resistance, offering a promising approach to cancer therapy. FMD, if combined with treatments like pharmacological doses of ascorbate could effectively target NSCLC rewired metabolism that sustains NSCLC progression. In this thesis, I investigated the combinatorial effects of FMD and pharmacological doses of vitamin C in KRAS-mutant NSCLC. In vitro, short-term starvation (STS) synergized with vitamin C to induce dramatic cell death in KRAS-mutant and wild- type NSCLC cell lines, while protecting normal cells. In vivo, cycles of FMD combined with high-dose vitamin C significantly delayed tumor growth in both immunodeficient (NSG) and immunocompetent (C57BL/6) mouse models, without inducing major toxicity. However, as previously demonstrated in our studies, cancer cells resist FMD through upregulation of starvation escape pathways. Here, mechanistically, RNA sequencing (RNA-seq) analysis revealed that resistant subpopulations upregulated MAPK signaling as an acute adaptive response, while chronic exposure drove additional activation of PI3K-AKT pathways to resist FMD and vitamin C treatment. Pharmacological blockade of EGFR/ERK (Afatinib, Ulixertinib) or PI3K (Pictilisib), particularly in dual ERK/PI3K inhibition, synergized with FMD and vitamin C to overcome…
author: SHMAHALA, ANASTASIYA
language: eng
keywords: oncology, nutrition, fasting, diet, resistance, oxidative stre, lung cancer, KRAS oncogene, ascorbate, metabolism, Settore MEDS-02/A - Patologia generale
date published: 2025-12-17
date modified: 2026-07-27T20:19:08Z
provider: Università degli Studi di Milano
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Università degli Studi di Milano

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property ID: Handle
value: https://hdl.handle.net/2434/1197878