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Cellular Senescence in Non-Small Cell Lung Cancer: from mechanisms to therapeutic opportunities


Type

Thesis

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Authors

González-Gualda, Estela 

Abstract

Lung cancer is the leading cause of cancer-related deaths in our society due to the inefficiency of early detection strategies and the high rate of treatment failure. Therefore, a better understanding of the mechanisms underlying its origin and the response to current treatment paradigms are crucial to improve lung cancer survival. Cellular senescence is a powerful tumour-suppressive mechanism whereby cells stably enter a cell-cycle arrest in response to oncogenic stress. However, the accumulation of senescent cells can alter the tumour microenvironment through a strong paracrine secretion of factors that can lead to detrimental and tumour-promoting effects. Intriguingly, senescence has been reported to be a defining feature of early lesions in Non-Small Cell Lung Cancer (NSCLC), a subtype that accounts for over 80% cases of lung cancer. In addition, senescence has also been reported to occur in response to the standard of treatment for this disease. It is thus conceivable that senescence may play a role in the origin and progression of this disease, despite a causal connection remains to be deciphered. Pharmacologic therapeutics that preferentially target senescent cells, known as senolytics, have been successful in preventing and even reversing senescence-driven detrimental effects in multiple pathological processes. However, their suboptimal specificity and toxicities hamper their clinical translation. Therefore, the targeting of senescent cells through the development of second-generation senolytics that can overcome these obstacles has the potential to revolutionise cancer treatment. The aim of this work is to define the role of cellular senescence at the origin and progression of lung cancer and in response to chemotherapy, and to develop safer and more effective therapeutic approaches to eliminate senescent cells in the context of lung malignancies. In this thesis, we studied the accumulation of senescent cells during the development of lung adenocarcinoma using a KrasG12V-driven lung cancer mouse model. We demonstrate that senolytic treatment of early lesions results in a significant reduction in lung tumour burden and increased survival, providing evidence of the tumour-promoting effect of senescence in early stages of NSCLC. Our research also reveals that platinum-based chemotherapy of human and murine lung adenocarcinoma cells induces senescence, which in turn promotes malignant phenotypes on untreated cancer cells in a paracrine manner in vitro, in xenografts and in orthotopic models of lung adenocarcinoma. Through high throughput unbiased transcriptomic and proteomic approaches, we show that secreted TGF-β ligands activate the Akt/mTOR pathway in untreated cells resulting in enhanced tumour growth. We further demonstrate that senolytic treatment and pharmacologic inhibition of TGFβR1 in tumours can prevent increased proliferation and enhance survival of lung tumour-bearing mice. In order to develop a novel approach for improved senolytic treatment, we show that the galacto-conjugation of senolytic ABT-263 (navitoclax) in the form of an activatable pro-drug significantly enhances cytotoxicity in combination with cisplatin, resulting in reduced lung cancer tumour growth. Importantly, our approach demonstrates decreased navitoclax-associated toxicities, including platelet apoptosis in human and murine blood treated ex vivo and decreased thrombocytopenia in mouse lung cancer models.
In summary, this PhD thesis provides evidence of the incidence and role that cellular senescence plays in promoting the progression of early and advanced NSCLC and demonstrates that cisplatin chemotherapy drives pro-tumorigenic phenotypes in a paracrine fashion, which can be prevented with senolytic and TGFβR1 inhibitory treatments. Lastly, it proposes a novel second-generation therapeutic approach to mitigate senolytic toxicities and enhance the efficiency of targeting senescence in the context of lung cancer.

Description

Date

2022-07-04

Advisors

Muñoz-Espín, Daniel

Keywords

cancer, senescence, lung, senolytic, therapy

Qualification

Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge