Molecular mechanisms driving aberrant activation of EGFR pathway: implications for cancer treatment

Gelfo, Valerio (2021) Molecular mechanisms driving aberrant activation of EGFR pathway: implications for cancer treatment, [Dissertation thesis], Alma Mater Studiorum Università di Bologna. Dottorato di ricerca in Oncologia, ematologia e patologia, 33 Ciclo. DOI 10.48676/unibo/amsdottorato/9888.
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Epidermal Growth Factor Receptor (EGFR) activates a robust signaling network to which tumors often become addicted. Over the last three decades, EGFR targeting has been intensely pursued as a treatment strategy for metastatic colorectal cancer (mCRC). One approach uses monoclonal antibodies (mAbs) to inhibit the extracellular domain of EGFR, thus blocking natural ligands binding. Unfortunately, patients often develop resistance, with consequent tumor growth and relapse. Tumors heterogeneity has been addressed as the main culprit for multiple escaping mechanisms, reflecting the high level of molecular heterogeneity in each metastatic site. Mechanisms of cancer cell resistance include either acquisition of new mutations or non-genomic activation of alternative signaling routes and, in this context, a role of IL-1 is emerging. For example IL-1 expression proved to be elevated in human breast, colon, lung and head and neck cancers, and patients with IL-1 producing tumors have generally bad prognosis. Our studies, performed with a cohort of 150 colorectal cancer xenopatients, associate poor response to CTX with increased abundance of a set of inflammatory cytokines, including IL-1A, IL-1B and IL-8. Stemming from these observations, our working hypothesis assumes that resistance to CTX is acquired, in a subset of CRC patients, through cell plasticity and consequent rewiring of signalling networks, which confer dependency on the IL1 pathway. This hypothesis foresees an auto-stimulatory feedback loop dependent on the IL-1 produced by the tumors, with consequent immunosuppression and tumor progression. Thus, combining IL-1 and EGFR neutralization may synergistically impair CRC response to CTX in vivo.

Tipologia del documento
Tesi di dottorato
Gelfo, Valerio
Dottorato di ricerca
Settore disciplinare
Settore concorsuale
Parole chiave
EGFR, Cetuximab, Resistance, IL-1, In vivo, Recombinant Decoy, TRAP IL-1
Data di discussione
22 Ottobre 2021

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