CCSG Pilot: Targeting p53/ERK1/2/DKK1 Axis for Overcoming Acquired Resistance to Chemotherapy in CRC

ABSTRACT Colorectal cancer (CRC) remains a significant contributor to morbidity and mortality and is the third most frequently diagnosed cancer. Metastatic CRC is prevalent, with approximately 22% of patients diagnosed at the time of presentation and up to 70% of patients experiencing metastatic relapse despite receiving surgery, chemotherapy, and radiotherapy. Most patients with metastatic CRC receive a combination of 5-fluorouracil (5- FU) and leucovorin (LV), along with oxaliplatin (FOLFOX) and irinotecan (FOLFIRI). However, application of these schemes to CRC patients often results in the development of chemoresistance, leading to therapy failure. A major contributing factor to tumor resilience and relapse is the presence of a “plastic” tumor microenvironment (TME), which is comprises heterogeneous stromal cell populations. Cancer-associated fibroblasts (CAFs), the most abundant stromal cells in the TME, are known to secret chemokines and cytokines such as Dickkopf-1 (DKK1) which promote immunosuppression and cancer relapse. Nevertheless, whether chemotherapeutic agents stimulate CAFs to reprogram their biological functions contributing to cancer progression and chemoresistance remains to be understood. We have discovered that the levels of DKK1 in the CRC stroma increase significantly in CRC patients who received chemotherapy. Moreover, we have obtained compelling data demonstrating that chemotherapeutic agents (5-FU, oxaliplatin, and irinotecan) stimulate CAF producing and secreting DKK1 to promote chemotherapy resistance. Therefore, our central hypothesis is that targeting DKK1 has the potential to create a drug-sensitive TME that sensitizes CRC to chemotherapeutic agents and increases their response rate. The hypothesis will be examined with the following two Specific Aims. In Aim 1, we will define the biological significance of chemotherapy-induced DKK1 in regulating immunosuppressive TME. We will first determine the contribution of CAF-secreting DKK1 to the maintenance of immunosuppressive TME. We will then determine the mechanisms by which chemotherapeutic agents induce DKK1 production in CAFs. In Aim 2, we will determine whether targeting DKK1 will enhance the efficacy of chemotherapy for CRC treatment. The expected outcomes are to be an in-depth mechanistic characterization of the complex interactions among CAFs, chemotherapy agents, and the TME that promote growth and drug resistance in CRCs. Accomplishment of these outcomes will provide a fundamental rationale for targeting DKK1 that could destroy the tumor niche and will lead to improved therapeutic strategies to treat CRC. Given that 5-FU, oxaliplatin, and irinotecan are also used in other malignancies (e.g., pancreas, gastric, biliary, breast, head and neck), our studies have treatment implications well beyond CRCs. To conduct this project, we have assembled a multidisciplinary team of researchers across the Molecular and Cellular Oncology (Wang) and Translational Oncology (Evers) Research Programs at the Markey Cancer Center. The Biospecimen Procurement and Translational Pathology, Biostatistics and Bioinformatics, and Flow Cytometry and Immune Monitoring Shared Resources will be used in this project.