Targeting ALC1 for synthetic lethality in cancer

Sahiri, Katharina Arien (2026): Targeting ALC1 for synthetic lethality in cancer: a superior alternative to PARP inhibitors. Dissertation, LMU München: Medizinische Fakultät

Abstract

Poly(ADP-ribose) polymerase inhibitors (PARPi) have shown great potential in cancer treatment by selectively targeting DNA repair pathways and inducing synthetic lethality, leading to improved patient outcomes. However, their non-specific inhibition of PARP activity presents challenges such as drug resistance, undesirable toxicities, and disruption of crucial cellular housekeeping functions performed by PARP1. To address these challenges, there is a current focus on targeting new downstream targets that can offer more precise and targeted inhibition. Among the emerging candidates is ALC1 (Amplified in Liver Cancer 1), an ATP-dependent chromatin remodeler linked to DNA repair processes. The poly-ADP-ribose (PAR)-activated remodeler ALC1 impacts DNA lesion accessibility through nucleosome sliding and is a synthetic-lethal vulnerability in homologous recombination-deficient (HRD) cancers. Eisbach Bio GmbH has developed ALC1 inhibitors (ALC1i), a new class of synthetic lethal medicines aiming to target the same genetic vulnerabilities as PARP inhibitors but in a more specific manner. In this thesis, inhibitors were employed to investigate the therapeutic potential of ALC1 inhibition in cancer treatment. In cellular contexts, ALC1i led to accumulation of DNA damage, changed DNA repair protein dynamics at DNA damage sites, and trapped PARPs on chromatin. This resulted in tumor-cell-specific synthetic lethality and, consequently, tumor cell death of HR-deficient over HR-proficient cells with a >20-fold selectivity. Further analysis of cell lines under ALC1i showed sensitivity in cancer cells extending beyond HRD. Importantly, ALC1 inhibition remained effective against PARP inhibitor-resistant cells. Combination treatments involving ALC1i showed synergistic effects with various approved chemotherapeutics and investigational agents, including PARPi. Moreover, when combined with Topoisomerase 1 inhibitors (TOP1i), like irinotecan, ALC1i showed high synergistic potential. In xenograft models, ALC1i have demonstrated great efficacy as a monotherapy, significantly reducing tumor growth. Despite the effective trapping of PARP on chromatin at DNA damage sites by ALC1i there were no apparent toxic side effects. This observation indicates that the toxicity associated with PARP inhibition may be linked more to its housekeeping functions rather than the process of trapping itself. The outcomes of this study emphasize the prospective value of ALC1 inhibition as a novel and promising therapeutic approach in cancer treatment and personalized medicine. The observed tumor-cell-specific synthetic lethality, along with the demonstrated effectiveness in diverse cancer contexts, positions ALC1 inhibition as a noteworthy candidate for further exploration and development in the pursuit of advanced cancer therapies.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 16. Januar 2026
• 1. Bericht­erstatter:in: Ladurner, Andreas