Role of pycr phosphorylation in chemoimmunotherapy resistance

The National Cancer Institute awarded Emory University $100,228 under the Cancer Research Manpower program (CFDA 93.398) on December 1, 2026, to support research training in biomedical careers relevant to the National Cancer Program.

The award funds investigation of PYCR phosphorylation in chemoimmunotherapy resistance, specifically examining how fibroblast growth factor receptor 1 (FGFR1) phosphorylates proline cycle regulatory enzymes (PYCR1 and PYCR2) and confers resistance to combined chemotherapy and immunotherapy in lung cancer. The research includes in vivo studies testing pharmacological PYCR inhibition to sensitize tumors to anti-PD1-based immunotherapy, with preliminary findings suggesting that targeting PYCR restores tumor responsiveness to immunotherapy in mouse models.

The period of performance runs through June 7, 2028, with place of performance in Atlanta, Georgia. The Cancer Research Manpower program supports biomedical training opportunities at nonprofit and for-profit institutions for individuals pursuing careers in basic, clinical, and prevention research aligned with National Cancer Program priorities. All competitive applications undergo evaluation by scientific authorities and review by the National Cancer Advisory Board, with selection based on scientific merit, program relevance, and program balance consistent with NCI and NIH strategic plans.

Abstract

Lung cancer is the primary cause of cancer mortality in the united states and around the globe. In the clinic, a combination of chemotherapy and immunotherapy (chemoimmunotherapy) has become a first-line therapy for patients with low predictive markers. However, patients often relapse due to the development of resistance, leading to therapeutic failure. Thus, characterizing cellular pathways that confer chemoimmunotherapy resistance is vital for improving cancer outcomes. Cellular metabolism and tyrosine kinase signaling are often dysregulated in human cancers, but the connection between these two in drug resistance remains undefined. To identify novel metabolic factors that are phosphorylated, leading to cancer cell survival under chemoimmunotherapy pressures, we established chemoimmunotherapy-naïve and therapy-resistant lung tumors in mice. Tyrosine-phosphorylated proteins were enriched from the tumors and analyzed by mass spectrometry. We found that enzymes within the mitochondrial proline metabolism pathway were exclusively phosphorylated in chemoimmunotherapy-resistant tumors. A preliminary in vitro kinase assay screening revealed that fibroblast growth factor receptor 1 (FGFR1), commonly upregulated in human cancers, can phosphorylate PYCR1 and PYCR2 at tyrosine sites 135 and 180, respectively, in human lung cancer cells. When these tyrosine sites in PYCR1/2 were mutated to phenylalanine, rendering them unable to be phosphorylated, in cancer cells, we observed a decrease in pycr activity, as assessed by intracellular proline levels. Furthermore, when FGFR1 was overexpressed or pharmacologically inhibited, the pycr activity increased and decreased, respectively. Our pilot in vivo study suggested that pharmacological targeting of pycr with a small molecule inhibitor pycr- in-1 sensitized tumors to anti-PD1-based immunotherapy. Thus, in this proposal, i will study how FGFR1 induced pycr phosphorylation induces pycr activation and chemoimmunotherapy resistance in vivo. Additionally, i will determine the therapeutic efficacy of targeting the FGFR1-pycr axis as a chemoimmunotherapy sensitizer, using specific inhibitors pycr-in-1 and dovitinib. The specific aims of the proposed research are 1) to decipher the mechanism by which FGFR1-mediated phosphorylation and activation of PYCR1/2 lead to chemoimmunotherapy resistance and 2) to evaluate the therapeutic efficacy of targeting pycr in enhancing chemoimmunotherapy response in lung cancer. In the long term, this proposal will not only provide information about the role of FGFR1-pycr in chemoimmunotherapy resistance but also a new actionable approach to improve the treatment outcome of lung cancer that is not responsive to chemoimmunotherapy.