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

Description du projet

Atténuer la réponse SOS pour vaincre la résistance aux médicaments anticancéreux

La résistance aux médicaments est un défi pour les patients atteints de cancer, en particulier ceux qui sont traités avec des inhibiteurs de tyrosine kinase (ITK), car les cellules cancéreuses activent des réponses SOS responsables de mutations. Le blocage du médiateur AXL peut prévenir les rechutes dues aux inhibiteurs de l’EGFR. Or, les traitements actuels ne font que retarder la résistance. Le projet ResistSOS, financé par le CER, va développer des stratégies qui minimisent la réponse SOS en combinant ces TKI efficaces mais mutagènes avec des médicaments conçus pour désarmer les mutateurs. Le projet concentrera ses recherches sur le cancer du poumon EGFR+, qui développe fréquemment une résistance. Il fait appel à des outils omiques pour déterminer exactement pourquoi le cancer ne répond plus au traitement. Ces connaissances permettront de tester de nouveaux moyens de bloquer les systèmes de réparation et les signaux de croissance du cancer, tout en entraînant le système immunitaire à attaquer la tumeur.

Objectif

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.