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Donald W. Kufe, MD



  • Distinguished Physician, Dana-Farber Cancer Institute
  • Professor of Medicine, Harvard Medical School

Contact Information

  • Office Phone Number(617) 632-3141
  • Fax(617) 632-2934


Dr. Kufe received his MD in 1970 from the University of Rochester School of Medicine. After a clinical fellowship in medical oncology at Dana-Farber Cancer Institute, he joined the staff in 1979. He has served as chief of the Division of Cancer Pharmacology, deputy director of the Dana-Farber Cancer Center, director of the Harvard Phase I Oncology Group and leader of the Experimental Therapeutics Program. He is an editor of the textbook "Cancer Medicine."

Recent Awards:

  • Richard P. and Claire W. Morse Scientific Award, DFCI 1997
  • Faculty Research Award, American Cancer Society 1982
  • Scholar Award, Burroughs-Wellcome 1986
  • Lung Cancer Research Foundation, Scientific Merit Award 2010


Identification and characterization of the oncogenic MUC1-C protein. The Kufe laboratory identified DF3/MUC1 in the 1980s as a glycoprotein that is aberrantly overexpressed in ~90% of human breast cancers. Cloning of the DF3/MUC1 gene further identified a unique physical structure comprised of 20 amino acid tandem repeats. Subsequent work showed that MUC1 is a complex consisting of an extracellular N-terminal subunit with glycosylated tandem repeats (MUC1-N; the mucin component) and a C-terminal transmembrane subunit (MUC1-C; the signaling component). In providing protection from the external environment, normal epithelial cells respond to stress with release of MUC1-N into the protective mucous barrier and MUC1-C functions in the transduction of signals to the interior of the cell to promote loss of polarity and induce wound healing and repair. Appropriation of this response by overexpression of MUC1-C, as found in carcinoma cells, was shown to be sufficient for inducing anchorage-independent growth and tumorigenicity, providing the first evidence that MUC1-C functions as an oncoprotein.

MUC1-C activates cell membrane and nuclear signaling pathways. Subsequent work demonstrated that MUC1-C drives loss of polarity, forms complexes with RTKs, such as EGFR, HER2 and others at the cell membrane, and contributes to their activation. These findings were extended by the demonstration that MUC1-C transduces signals from the cell membrane to the nucleus. As one example, MUC1-C was found to directly activate the proinflammatory IKK→NF-κB→p65 pathway, form complexes with p65 on promoters of target genes and contribute to their regulation. Other work showed that MUC1-C promotes the inflammatory response through activation of nuclear STAT1/3 signaling pathways, supporting the notion that MUC1-C contributes to the association between inflammation and cancer.

MUC1-C induces EMT, self-renewal and epigenetic reprogramming. The Kufe laboratory first demonstrated that MUC1-C functions in the regulation of genes that drive EMT and self-renewal of cancer stem-like cells. Further work linked MUC1-C to epigenetic reprogramming by showing that MUC1-C regulates DNA methylation by activating the DNMT1 and DNMT3b genes. Advances also included unrecognized roles for MUC1-C in activating the PRC1/BMI1 and PRC2/EZH2 complexes in driving the repression of tumor suppressor genes, such as such as CHD1, CDKN2A, PTEN, BRCA1 and RASSF1A. Other studies showed that MUC1-C activates the highly conserved NuRD complex, which regulates chromatin assembly and reorganization and is of importance for EMT and invasion. These findings linked MUC1-C to integrating DNA methylation, histone regulation and chromatin remodeling in cancer cells.

MUC1-C promotes genotoxic and targeted drug resistance. The early finding that MUC1-C confers resistance to genotoxic anti-cancer agents was attributed in part to suppression of the DNA damage-induced apoptotic response. Other work in this area extended involvement of MUC1-C in the repair of DNA damage and, more recently, the integration of chromatin remodeling in that response. Other studies showed that MUC1-C confers resistance to targeted agents, such as trastuzumab, tamoxifen, afatinib and others, and that targeting MUC1-C is synergistic with these agents in resistant cells.

MUC1-C inhibits immune recognition and destruction. The Kufe laboratory first demonstrated that MUC1-C activates the PD-L1 gene and represses expression of immune effectors in cancer cells. In concert with these functions, targeting MUC1-C with a novel inhibitor downregulates PD-L1 in mouse tumor models and activates CD8+ T-cells in the immune microenvironment. In addition, MUC1 expression in human cancers correlates negatively with that of the CD8 and IFNγ genes and is associated with poor clinical outcomes. These findings provided the first evidence that MUC1-C plays a role in immune evasion.

MUC1-C drives dedifferentiation and pluripotency cancer cells. Understanding how MUC1-C drives cancer cell plasticity and the multiple above hallmarks of the cancer cell is of critical importance. The Kufe laboratory has found that MUC1-C induces dedifferentiation and pluripotency of breast and prostate cancer cells. In this way, MUC1-C drives stemness in association with induction of Yamanaka pluripotency factors, which have been shown to confer lineage plasticity and dedifferentiation of fibroblasts. These findings have uncovered new lines of ongoing investigation to more precisely define how MUC1-C integrates dedifferentiation, stemness and pluripotency in cancer.

Targeting MUC1-C with agents under development. There are presently no clinically available 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 CAR T-cells, BiTEs and antibody-drug conjugates. 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.

Kufe Lab Contributions

1980’s            1990’s            2000’s            2010's            2020’s



Identification of human DF3/MUC1 carcinoma-associated antigen.  Overexpression in diverse carcinomas.




Development of first blood test (CA15-3) for monitoring MUC1 levels and thereby the clinical course of patients with cancer.


Cloned the MUC1 cDNA. Identified the 20 amino acid tandem repeats in the MUC1 N-terminal ectodomain.  Identified sequences in the transmembrane domain and cytoplasmic tail.



Demonstrated that overexpression of MUC1 in carcinomas is regulated by transcriptional activation of the MUC1 gene.


Identified unmasking of a MUC1 epitope (DF3-P) by aberrant glycosylation in human carcinomas.


Characterization of cis-acting elements regulating MUC1 gene transcription.


Developed carcinoma-selective gene therapy approach using the MUC1 promoter.



Demonstrated that MUC1 is a signaling molecule and putative oncogene.


Developed novel approach for targeting carcinoma cells based on MUC1 promoter-driven somatic gene transfer.


First demonstration that fusions of dendritic cells and tumor cells can be used in the treatment of cancer.  Approach shown to induce immunity against MUC1.


Demonstrated that the MUC1 cytoplasmic tail interacts with       b-catenin, an effector of the Wnt signaling pathway.


Reversed tolerance to human MUC1 antigen in MUC1 transgenic mice immunized with fusions of dendritic and carcinoma cells.



Demonstrated that fusions of primary human carcinoma cells and dendritic cells activate T cell responses against autologous tumors.


Developed a replication-competent adenovirus selective for carcinomas expressing MUC1.


Demonstrated that MUC1 interacts with the epidermal growth factor receptor (EGFR) and the c-Src tyrosine kinase.


Demonstrated that phosphorylation of the MUC1 cytoplasmic tail by protein kinase C regulates the interaction between MUC1 and      b-catenin.


Showed that MUC1 interacts with ErbB2 and functions as an oncoprotein.


Demonstrated that the MUC1 C-terminal subunit localizes to the nucleus and functions as a coactivator of transcription.


Demonstrated that MUC1 confers resistance to genotoxic anti-cancer agents.


Showed that MUC1 confers resistance to oxidative stress-induced apoptosis and necrosis.



Demonstrated that MUC1 binds directly to p53 and attenuates p53-dependent apoptosis in response to genotoxic stress. 


Demonstrated that MUC1 stabilizes b-catenin and thereby contributes to transformation.


Demonstrated that MUC1 stabilizes ERa and coactivates ERa-mediated gene transcription.


Demonstrated that MUC1 blocks function of the proapoptotic c-Abl tyrosine kinase in the response to genotoxic anticancer agents.


Showed that the MUC1-C subunit undergoes dimerization through a CQC motif in the cytoplasmic domain.  Dimerization is necessary for its oncogenic function.  


Demonstrated that the MUC1-C subunit activates the IKK complex and NF-kB signaling.


Demonstrated that MUC1-C stabilizes Bcr-Abl and contributes to the pathogenesis of CML.


Demonstrated that MUC1 promotes growth and survival of multiple myeloma cells.


Developed the first direct inhibitor of the MUC1-C cytoplasmic domain and showed activity against breast and prostate cancer in vitro and in animal models.



Showed that targeting of the MUC1-C cytoplasmic domain induces death of multiple myeloma and CML cells.


Demonstrated that MUC1-C activates the STAT3 pathway.


Showed that MUC1-C suppresses ROS-mediated differentiation of AML cells. 


Identified small molecule inhibitors of the MUC1-C cytoplasmic domain.


Demonstrated that MUC1-C drives TIGAR expression and thereby protects against ROS in multiple myeloma cells.


MUC1-C forms homodimers that are dependent on the CQC motif and redox imbalance.


Demonstrated that MUC1-C confers resistance to tamoxifen in breast cancer cells.


Reported that MUC1 is expressed in the AML stem cell and is a target for eliminating this population.


Demonstrated that MUC1-C drives the epithelial-mesenchymal transition (EMT) by a ZEB1 mechanism.


Showed that MUC1-C promotes resistance to traztuzumab in HER2-positive breast cancer cells.



Demonstrated that MUC1-C activates the TAK1"IKK"NF-kB p65 inflammatory pathway.


Formulation of the MUC1-C inhibitor GO-203 in polymeric nanoparticles for sustained delivery.


Showed that MUC1-C drives MYC expression in NSCLC and multiple myeloma cells.


Demonstrated that MUC1-C functions in epigenetic regulation by activating DNA methylation and BMI1/PRC1.


Demonstrated that MUC1-C induces PD-L1 in NSCLC and promotes immune evasion.


Extended the role of MUC1-C in epigenetic regulation by inducing EZH2 and other members of the PRC2 complex.


Showed that MUC1-C promotes the immunosuppressive tumor microenvironment in models of NSCLC.


Showed that MUC1-C promotes the immunosuppressive tumor in macroenvironment in TNBC.


Developed MAb 3D1 to target the MUC1-C extracellular domain with an ADC and CAR-Ts


Demonstrated that MUC1-C is involved in the DNA damage response (DDR) in association with PARP.


Reported that MUC1-C integrates EMT, the CSC state and drug resistance in TNBC.


Documented a role for MUC1-C in lineage plasticity of TNBC and NEPC cells.


Research Focus

Role of MUC1-C in cancer cell differentiation, stemness and pluripotency.



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