Abstract SY39-02: Accessing evolutionary programs to enable therapeutic resistance

Abstract

Abstract Twenty million people around the world are diagnosed with cancer every year and over ten million people die because their cancer has metastasized and is incurable using current systemic therapies. Metastatic disease remains incurable because tumors evade all forms of programmed cell death. How is this possible? Unicellular and multicellular organisms have evolved multiple strategies to avoid death from internal and external stresses. While the nature of these catastrophes may be varied, their common property is to doom the organism unless it can access a survival mechanism and/or evolve a resistance mechanism rapidly. One such stress survival mechanism that is present across the tree of life in both unicellular and multicellular organisms is the utilization of a program that enables whole genome doubling (polyploidization) and cell cycle arrest. This evolutionary program allows the organism to avoid environmental stresses and protect the integrity of its genomic material by adopting a quiescent phenotype. In addition, by doubling DNA and increasing RNA and protein material, organisms have increased capacity to evolve further resistance mechanisms to stressors. To date, no common genomic signature has been defined that can explain or identify which patients will develop therapeutically resistant and lethal metastatic cancer. In all these incurable patients, therefore, lethal cancer independently evolves capacities for metastasis, avoidance of all cellular death pathways, and resistance. This convergent outcome across all patients demands an explanation beyond the accrual of stochastic mutations. Since the tumor ecosystem is exposed to constantly changing chemical and biologic conditions, it is generally assumed that cancer cell populations must have the ability to evolve rapidly to acquire mutations to adapt and survive. An alternative and complementary theory to explain cancer cell fitness is that a subset of cancer cells access evolutionary stress survival programs that are inherited as development programs. These development programs enable whole genome doubling (polyploidization) and cell cycle arrest and are seen in multiple cell types, including regenerating liver cells, myocytes under physical strain, and megakaryocytes under metabolic stress. In cancer, access to these stress programs result in cancer cell survival though a state of cell cycle arrest that is simultaneously polyploid and aneuploid. Entering the polyaneuploid cancer cell (PACC) state, cancer cells pause their cell cycle and protect the integrity of their DNA from tumor microenvironmental stresses as well as have increased potential to develop further resistance mechanisms to environmental stressors and toxic therapies. After stress is removed, cells in the PACC state undergo depolyploidization and generate resistant progeny. This enables the generation of heritable variation that can be dispensed to their 2N+ aneuploid progeny, providing population rescue in response to therapeutic stress. Targeting cells in the PACC state opens a new avenue for cancer therapy. Citation Format: Kenneth J. Pienta. Accessing evolutionary programs to enable therapeutic resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY39-02.