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

Project Information

ResistSOS

Grant agreement ID: 101097332

DOI

10.3030/101097332

EC signature date 24 May 2023

Start date 1 October 2023

End date 31 July 2028

Funded under

• European Research Council (ERC)

Total cost

€ 2 500 000,00

EU contribution

€ 2 500 000,00

Coordinated by

WEIZMANN INSTITUTE OF SCIENCE
Israel

Periodic Reporting for period 1 - ResistSOS (Overcoming Resistance to Anti-cancer Drugs by Blocking Mutation-prone DNA Polymerases and the SOS Response)

Reporting period: 2023-10-01 to 2026-03-31

Summary of the context and overall objectives of the project

Cancer of the lungs is driven primarily by polluted air from power houses and vehicles, as well as tobacco smoking. One way to classify the different types of lung cancer is based on the type of mutations that fuel the disease. For example, our ERC-supported project focuses on a type of lung cancer that is driven by a group of DNA defects collectively called EGFR mutations. Unlike the lung cancer of tobacco smokers, the class of EGFR-mutations is likely driven by tiny particles found in diesel exhaust and in other air pollutants. Fortunately, nearly 20 years ago some highly effective and relatively safe drugs were developed that prolonged the life expectancy of the respective patients. However, it was later found that almost all patients treated with the effective drugs, denoted EGFR inhibitors (EGFRi), become resistant to the drug. This necessitated development of new drugs. Similar to the first-generation drugs, the new drugs also achieved high efficacy and high safety. Unfortunately, however, patients treated with the new generation drugs also evolved resistance, and like in the first cycle, this was due primarily to the emergence of new mutations.

Along with the development of yet new drugs, a major mission currently undertaken by the pharmaceutical sector and the academic sector, including our ERC-supported team, concentrates on the mechanisms that propel the emergence of new mutations in patients undergoing treatment with EGFR inhibitors. Apparently, several biochemical mechanisms underlie the rapid generation of mutations in patients with lung cancer (approximately one year). Several years ago, we discovered that one mechanism undergoes activation when cancer cells are on the verge of dying due to the treatment with the first- or second-generation drugs. The mechanism, called SOS, is the major focus of our studies. Presumably, resolving the intricacies of the SOS process might identify ways to prevent emergence of new mutations. In other words, it is assumed that deep understanding of the SOS process will allow development of new drugs, or drug combinations, that are able to overcome or significantly delay the timing of the emergence of the new mutations.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The work performed might be divided in two parts: (i) attempts to resolve mechanisms underlying resistance to EGFR kinase inhibitors, and (ii) attempts to generate new molecular entities able to inhibit resistance to EGFR kinase inhibitors. The first part has focused on the role played by STING and mutagenic DNA polymerases. These efforts are currently ongoing but it seems that they are linking drug-induced reactive oxygen species (ROS), DNA double strand breaks and formation of circular extrachromosomal DNA to chromothripsis and gene amplification/mutagenesis. The therapeutic part has focused on a group of compensatory receptors that includes AXL, HER2, HER3, MET and the IGF1-receoptor. We are generating bispecific antibodies against these receptors, as well as biparatopic antibodies that are covalently linked to chemotherapeutic drugs targeting the cytoskeleton and spindle formation.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The involvement of ROS-induced DNA breaks, as well as the emerging roles for STING, go beyond the state of the art. Likewise, the polymerases we will likely identify will lead us to the identification of targetable enzyme inhibitors and novel strategies to prevent or delay tumor relapses. The part dealing with compensatory receptors is also promising and might generate therapeutic breakthroughs in the form of specific recombinant antibodies or combinations of antibodies and small molecule drugs.