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

Projektinformationen

ResistSOS

ID Finanzhilfevereinbarung: 101097332

DOI

10.3030/101097332

EK-Unterschriftsdatum 24 Mai 2023

Startdatum 1 Oktober 2023

Enddatum 31 Juli 2028

Finanziert unter

• European Research Council (ERC)

Gesamtkosten

€ 2 500 000,00

EU-Beitrag

€ 2 500 000,00

Koordiniert durch

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)

Berichtszeitraum: 2023-10-01 bis 2026-03-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

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.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

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.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

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.