Abstract PO-070: Boost tumor response to radiation therapy: What can we learn from PTEN-deficient models?

Abstract

Abstract PTEN is among the most frequently mutated genes in nearly all types of cancer. TCGA studies reported mutation or deletion of the PTEN gene in 11% of breast invasive carcinoma and 9% of colorectal adenocarcinoma. Cancer-associated PTEN deficiency is associated with worse prognosis as well as tumor resistance to therapies, including chemotherapy and immunotherapy. However, it is largely controversial, as there is no consensus regarding how PTEN deficiency alters tumor response to radiation therapy (RT). RT elicits anti-cancer efficacy through both cell-autonomous and non-cell-autonomous mechanisms by disrupting the cancer genome and by promoting immune responses. Similarly, loss of PTEN results in genomic instability and immune deregulation, which may lead to a tumor-specific net outcome of growth and response to RT. In order to characterize a pan-cancer phenotype of RT sensitivity, we created multiple isogenic pairs of tumor cells of different tissue origins. Our studies, using both a breast cancer model and a colon cancer model, demonstrate that PTEN deficiency confers an enhanced RT efficacy through a non-cell autonomous mechanism. Specifically, orthotopically implanted tumors lacking PTEN regressed significantly following single-dose RT that was less effective in suppressing PTEN-proficient tumors. A more efficient regimen (3*8Gy) became ablative and achieved 100% tumor-free survival only in the hosts of PTEN-deficient tumors. The RT sensitivity manifested in PTEN-mutant tumors in vivo is likely due to enhanced immunogenicity, because in vitro, PTEN-deficient cancer cells not only lost such vulnerability but often exhibited RT resistance. Our data suggest that PTEN-deficient tumor phenotypes may be exploited to achieve the highest cancer elimination rate, using a combinatorial strategy to promote non-cell-autonomous immunogenicity and to concurrently overcome cell-autonomous RT resistance. Citation Format: Xinyi Fan, Miaoyan Qiu, Silvia C. Formenti, Wen H. Shen. Boost tumor response to radiation therapy: What can we learn from PTEN-deficient models? [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-070.