Kufe Lab Investigating the MUC1-C Oncoprotein as a Therapeutic Target in Cancer Treatment
Welcome to Kufe Lab
Donald Kufe, MD, is Professor of Medicine at Harvard Medical School, Distinguished Physician at the Dana-Farber Cancer Institute, and Co-PI of the Harvard/National Cancer Institute ETCTN UM1 Early Phase Trials Agreement. Dr. Kufe is a member of the NCI Investigational Drug Steering Committee (IDSC) and the Cancer Moonshot Initiative, NCI, Immuno-Oncology Translational Network (IOTN) Steering Committee.
Research in the Kufe laboratory led to identification of the DF3/MUC1 protein based on its overexpression in human breast and other carcinomas. Cloning of the MUC1 cDNA and work showing that MUC1 consists of highly glycosylated tandem repeats contributed to the classification of a genetically distinct family of over 20 secreted and transmembrane mucins.
Seminal advances in the field emerged with the findings that MUC1 is a heterodimeric complex and that the transmembrane MUC1-C subunit functions as an oncoprotein. Work in the Kufe laboratory defined how MUC1-C contributes to transformation by inducing loss of polarity, activating RTKs at the cell membrane and transducing signals to the nucleus. Findings that the intrinsically disordered MUC1-C cytoplasmic domain interacts with diverse kinases and effectors that have been linked to transformation also provided the basis for defining MUC1-C-induced activation of inflammatory signaling pathways that drive EMT, epigenetic reprogramming and self-renewal in carcinoma cells.
Stemness contributes to drug resistance and immune evasion by presently unclear mechanisms. Early studies from the Kufe laboratory showed that MUC1-C promotes resistance to anti-cancer agents by inhibition of the stress-induced apoptotic stress. MUC1-C also promotes the DNA damage repair response, supporting the premise that MUC1-C contributes to the progression of cancers refractory to conventional genotoxic agents. The Kufe laboratory further showed that MUC1-C drives resistance to targeted agents, such as those against EGFR and HER2, and that targeting MUC1-C is synergistic with those agents. Additionally, findings that MUC1-C drives immune evasion provided further support for the premise that MUC1-C drives a process of pluripotency that confers pleiotropic resistance of cancer cells to cytotoxic, targeted and immunotherapeutic agents.
There are presently no clinically approved therapeutic agents against the MUC1-C subunit. To address this unmet need, the Kufe laboratory has developed potential therapeutics that target the MUC1-C extracellular and cytoplasmic domains. The generation of monoclonal antibodies (MAbs) against the MUC1-C extracellular domain provided the basis for development of (i) allogeneic CAR T cells, now under Phase I evaluation, (ii) antibody-drug conjugates under development with the NCI NExT Program, and (iii) T cell engagers. A cell-penetrating peptide directed against the MUC1-C cytoplasmic domain CQC motif, which is necessary for MUC1-C homodimerization and oncogenic function, is also under development with NCI Moonshot funding based on its activity in suppressing MUC1-C-induced drug resistance and immune evasion.
In summary, the Kufe laboratory established and has continued to lead the field of research on the MUC1-C oncoprotein in human cancers.