Overcoming Resistance to Anti-cancer Drugs by Blocking Mutation-prone DNA Polymerases and the SOS Response

Descrizione del progetto

Ridurre la risposta SOS per superare la resistenza ai farmaci antitumorali

La resistenza ai farmaci rappresenta una sfida per i malati di cancro, in particolare per quelli in terapia con inibitori della tirosin-chinasi (TKI), poiché le cellule tumorali attivano risposte SOS che portano a mutazioni. Il blocco del mediatore AXL può prevenire le recidive indotte dagli inibitori dell’EGFR. Tuttavia, le terapie attuali non fanno altro che ritardare l’insorgenza della resistenza. Il progetto ResistSOS, finanziato dal CER, mira a sviluppare strategie che riducano al minimo la risposta SOS combinando questi TKI efficaci ma mutageni con farmaci progettati per neutralizzare i mutatori. Il progetto si concentrerà sul cancro al polmone EGFR+, che spesso sviluppa resistenza. Utilizza strumenti omici per individuare con precisione il motivo per cui il cancro smette di rispondere alle cure. Queste scoperte consentono di sperimentare nuovi modi per bloccare i meccanismi di riparazione e i segnali di crescita del cancro, addestrando al contempo il sistema immunitario ad attaccare il tumore.

Obiettivo

Background: A large fraction of cancer patients die because their tumors initially respond to drugs but later they evolve tolerance. Thus, resistance to diverse drugs, along with the soaring costs of new treatments, are emerging as major societal issues of the 2020s. Herein, we explore one of the most distressful examples, tolerance of lung cancer to EGFR-specific tyrosine kinase inhibitors (TKIs).
Working hypothesis: In similarity to bacteria exposed to antibiotics, when cancer cells are exposed to TKIs they enlist SOS responses, which activate endogenous mutators. Hence, we will combine the relatively effective but mutagenic TKIs with drugs that disarm the mutators. This scheme will be applied on models of EGFR+ lung cancer, a disease that repeatedly evolves mutations and resistance, but eventually leaves millions of patients with no treatment choices.
Specific aims: Our initial studies identified one triad of the SOS system: a sensor of cell death - GAS6, a mediator - AXL, GAS6’ receptor, and a mutator - low-fidelity DNA polymerases. Remarkably, blocking AXL using an antibody irreversibly prevented relapses when combined with EGFR inhibitors. Along with establishing this triad, we will employ transcriptomics, protetomics and metabolomics to resolve parallel mutators and sensors. Likewise, we will explore alternative ways to block resistance, for example by directly targeting DNA polymerases, MYC and purine metabolism. Aiming at strategies that minimize SOS enlisting, we will explore the premise of boosting immune destruction of cancer cells.
Significance: According to the current status quo, next-generation inhibitors are being applied when resistance emerges. However, this scheme does not cure, only buys time. ResistSOS offers an alternative that might eradicate resistance and cure disease models following treatments that are based on deep understanding and blocking the mutagenic SOS response.