One of the oncological diseases connected with a high number of environmental risk factors is lung cancer. With 18.7% of deaths, it is the leading cause of cancer-related death. Between 80-85% of all non-small cell lung cancer (NSCLC) cases, the most common lung cancer subtype, are correlated with direct cigarette consumption and secondhand smoke. Not only air but also some water pollutants as arsenic, are related to an increase in NSCLC cases. Since lung cancer has a significant social impact, it is crucial to expand our understanding of both environmental risk factor evaluation, including characterization of emerging water pollutants and their transformation products, and lung cancer treatment, including the assessment of novel therapeutic approaches to address drug resistance. The first part of my PhD was dedicated to the analysis of the toxic effects on human pulmonary epithelial cells, normal and oncogenic, of three water pollutants and their transformation products. The TPs were obtained with photocatalysis mediated by titanium dioxide. The selected compounds were i) ofloxacin, a synthetic fluoroquinolone commonly used to treat bacterial infections in the respiratory tract, kidney, urinary tract, skin, and soft tissue. ii) Ciprofloxacin, a second-generation fluoroquinolone used to treat a large number of bacterial infections, including lower respiratory tract infections, skin infections, intra-abdominal infections, and urinary tract infections. And iii) diclofenac, one of the most common NSAIDs, known also as the trade name of Voltaren, used to treat rheumatic pain and inflammation, but also osteoarthritis and rheumatoid arthritis. The already known TPs were analyzed in different environmental conditions to evaluate their stability over time. 37°C in the absence of light to simulate the cell growing conditions, and room temperature in the presence of natural light to simulate the environmental conditions. In both conditions, the parental compounds and TPs appear to be quite stable or present a slight decrease. Moreover, the acute toxicity was investigated on human pulmonary epithelial cells, normal BEAS 2B, and oncogenic BEAS 2B KRAS G12C. The results showed that the TPs derived from ciprofloxacin and ofloxacin, at high concentrations, strongly decrease the cell viability, while the diclofenac ones are less toxic even at higher concentrations. In the second part of my PhD, I evaluated new treatment strategies to overcome LUAD resistance to targeted therapies, in particular to KRAS G12C (OFF) inhibitors sotorasib and adagrasib, recently approved by the FDA. Two different resistant cell models were considered: one, acquired, in which the presence of in cis mutations (G12C/Y96D-R68S-H95Q-H95R) impaired drug binding to one or both of the inhibitors. The other, adaptive or induced, resistant cell models were generated through the chronic treatment with increasing concentrations of sotorasib or adagrasib till complete drug resistance was obtained. Acquired and induced models were treated with sequential treatment with approved KRAS-OFF inhibitors and a new generation of multi-RAS inhibitors to simulate clinical cases and propose a better solution to overcome the development of drug resistance. The results showed that in all considered cell models, the treatment with the pan-RAS RMC-7977 (ON) inhibitor is efficacious to overcome the developed resistance mechanism.

Identification of new therapeutic strategies for oncological diseases caused by pollution

VIETTI MICHELINA, SANDRA
2025

Abstract

One of the oncological diseases connected with a high number of environmental risk factors is lung cancer. With 18.7% of deaths, it is the leading cause of cancer-related death. Between 80-85% of all non-small cell lung cancer (NSCLC) cases, the most common lung cancer subtype, are correlated with direct cigarette consumption and secondhand smoke. Not only air but also some water pollutants as arsenic, are related to an increase in NSCLC cases. Since lung cancer has a significant social impact, it is crucial to expand our understanding of both environmental risk factor evaluation, including characterization of emerging water pollutants and their transformation products, and lung cancer treatment, including the assessment of novel therapeutic approaches to address drug resistance. The first part of my PhD was dedicated to the analysis of the toxic effects on human pulmonary epithelial cells, normal and oncogenic, of three water pollutants and their transformation products. The TPs were obtained with photocatalysis mediated by titanium dioxide. The selected compounds were i) ofloxacin, a synthetic fluoroquinolone commonly used to treat bacterial infections in the respiratory tract, kidney, urinary tract, skin, and soft tissue. ii) Ciprofloxacin, a second-generation fluoroquinolone used to treat a large number of bacterial infections, including lower respiratory tract infections, skin infections, intra-abdominal infections, and urinary tract infections. And iii) diclofenac, one of the most common NSAIDs, known also as the trade name of Voltaren, used to treat rheumatic pain and inflammation, but also osteoarthritis and rheumatoid arthritis. The already known TPs were analyzed in different environmental conditions to evaluate their stability over time. 37°C in the absence of light to simulate the cell growing conditions, and room temperature in the presence of natural light to simulate the environmental conditions. In both conditions, the parental compounds and TPs appear to be quite stable or present a slight decrease. Moreover, the acute toxicity was investigated on human pulmonary epithelial cells, normal BEAS 2B, and oncogenic BEAS 2B KRAS G12C. The results showed that the TPs derived from ciprofloxacin and ofloxacin, at high concentrations, strongly decrease the cell viability, while the diclofenac ones are less toxic even at higher concentrations. In the second part of my PhD, I evaluated new treatment strategies to overcome LUAD resistance to targeted therapies, in particular to KRAS G12C (OFF) inhibitors sotorasib and adagrasib, recently approved by the FDA. Two different resistant cell models were considered: one, acquired, in which the presence of in cis mutations (G12C/Y96D-R68S-H95Q-H95R) impaired drug binding to one or both of the inhibitors. The other, adaptive or induced, resistant cell models were generated through the chronic treatment with increasing concentrations of sotorasib or adagrasib till complete drug resistance was obtained. Acquired and induced models were treated with sequential treatment with approved KRAS-OFF inhibitors and a new generation of multi-RAS inhibitors to simulate clinical cases and propose a better solution to overcome the development of drug resistance. The results showed that in all considered cell models, the treatment with the pan-RAS RMC-7977 (ON) inhibitor is efficacious to overcome the developed resistance mechanism.
8-lug-2025
Inglese
DAL BELLO, Federica
Università degli Studi di Torino
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.14242/217890
Il codice NBN di questa tesi è URN:NBN:IT:UNITO-217890