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

Background

A large fraction of cancer patients die because their tumors initially respond to drugs but later 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’s receptor
• 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, proteomics, and metabolomics to resolve parallel mutators and sensors.

Likewise, we will explore alternative ways to block resistance, for example by directly targeting:

1. DNA polymerases
2. MYC
3. 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.