Abstract LB222: Elucidating the cellular responses and mechanism of action of 177Lu-based radioligand therapy

Abstract Radioligand therapy (RLT) is emerging as a safe and effective targeted approach for treating several types of cancers. Lutathera® (177Lu-Dotatate) and Pluvicto® (177Lu-PSMA-617) are two examples of FDA-approved 177Lu-based RLT drugs for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and of PSMA-positive metastatic castration-resistant prostate cancer (mCRPC), respectively. Despite the clinical success of 177Lu-RLT, there are still patients lacking complete, durable responses. Arguably, elucidating the cellular responses to 177Lu-RLT and its mechanism of action could reveal potential opportunities for the improvement of therapy and outcome for patients. We have investigated the phenotypes and responses of multiple 177Lu- RLT-treated cell lines and observed that 177Lu-RLT induces a plethora of DNA Damage Response (DDR) markers, especially those indicative of double-strand break (DSB) repair by either non-homologous end-joining (NHEJ) or homologous recombination (HR). Furthermore, 177Lu-RLT leads to cell-cycle alterations, accumulation of micronuclei and cell death. In agreement with published reports, we have observed that either the knock-out or inhibition of NHEJ core factors such as the catalytic subunit of DNA-PK (PRKDC) renders cells sensitive to 177Lu-RLT and the combination of both the 177Lu-RLT and DNA-PK inhibitor provides a beneficial tumor growth inhibition in vivo. To further unravel the mechanism of action of 177Lu-RLT, we have conducted ‘DDR-ome’ targeted genetic screens, which also suggest that DSBs are the most cytotoxic form of 177Lu-RLT-induced DNA damage. In addition to DNA-PK, we have identified novel DDR targets that could sensitize to 177Lu-RLT. We are currently testing whether inhibiting these targets in combination with certain 177Lu-RLT could, in addition to potentially achieving greater antitumor response, allow for lower dosing to reduce radiation exposure. Taken together, our work provides better understanding of the cellular responses to 177Lu-based RLT and pinpoints NHEJ as a critical pathway promoting survival to this treatment, which could set the basis for novel combination therapies. Citation Format: Marco Ranzani, Sravanth Hindupur, Alessandro Cicconi, Guillermo Sastre-Moreno, Alexander Kristian, Barbara Schacher Engstler, Benika Pinch, Charlene Hartnagel, Delphine Gorses, Elise Simon, Emeline Mandon, Emilien Schramm, Fanny Schaeffer, Josefine Reber, Louise Barys, Luisa Deberle, Milene Walter, Ralph Bessey, Riccardo Destefani, Xavier Miot, Elias Elinati, Nan Shao, Marie Boursier, Joseph Barlow, Asmita Thapa, Alessandro Galbiati, Diego Grande, Eeson Rajendra, Niall Martin, Graeme Smith, Tobias Schmelzle, Markus Reschke, Helen Robinson, Marta Cortes-Cros. Elucidating the cellular responses and mechanism of action of 177Lu-based radioligand therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB222.