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EGF family receptor tyrosine kinases in cancer

Figure 1: EGF family of hormones and receptors
Figure 1
Mutations in these receptor genes cause subsets of breast cancer, lung cancer, glioma, head and neck cancer, colorectal carcinoma, and other solid tumors. For this reason, drugs targeting these receptors are among the most important new cancer therapeutics. These drugs include Tarceva/Erlotinib, Tykerb/Lapatinib, Erbitux/Cetuximab, and Herceptin/Trastuzumab. For example, the receptor tyrosine kinase ErbB2/HER2 drives 25% of breast cancers. This receptor is the target for two drugs in use for breast cancer treatment, Herceptin and Tykerb. In order to understand why this receptor is so important in human cancer, and to improve therapeutic targeting of ErbB2/HER2, we investigate normal and pathological functions of this receptor in mammary tissue. Our work spans from fundamental studies on signal transduction to analysis of ErbB2 in human cancer. ErbB2 works in close partnership with other members of the EGF receptor (ErbB family) of tyrosine kinases, so we also study differential signaling by the three related receptors (EGF receptor [HER]), ErbB3 [Her-3], ErbB4[Her4).

Checkpoint controls

Figure 2: Nuclear Functions of erb-B-4
Figure 2
Function as quality controls that supervise cell cycle progression. Such controls are of great interest because of their role in cell cycle regulation, and because they are commonly altered in human cancer. We are investigating signal transduction in DNA checkpoint control pathways. This involves analysis of checkpoint signaling in both budding yeast and humans, with the focus on the double-strand DNA break response pathway encompassing tumor suppressor gene Atm and Chk2/Rad53, and mediator proteins NFBD1/MDC1, 53B1, BRCA1, and MCPH1.

Predicting sensitivity to molecularly targeted drugs

Figure 3: Mediators in yeast checkpoint signaling
Figure 3
The growing availability of cancer drugs that target receptors and other signaling proteins has created a need to develop integrated methods for best matching of patients to the appropriate target drugs. We are investigating use of DNA-based and functional approaches for predicting response to targeted therapies, in breast cancer and melanoma.

Current Projects

FIgure 4: Yeast checkpoint signaling cascade
Figure 4
  • ErbB4 is unique among receptor kinases in undergoing regulated cleavage to release an active intracellular domain. We are studying the nature of nuclear processes regulated by ErbB4, and the role of alternative splicing in generating functionally diverse forms of the receptor.
  • Excessive activity of growth factor receptors can lead to checkpoint arrest, selection for checkpoint bypass, and genomic instability. We are investigating the hypothesis that high-level signaling by ErbB2/HER2 promotes genomic instability, a hallmark of breast cancer and other solid tumors.
  • Our laboratory originally identified the importance of “mediator proteins” in transmission of checkpoint responses from sensor phosphatidyl inositol kinase-like kinases to effector checkpoint kinases through recognition of phospho-peptides. Ongoing work includes understanding differential activities of mammalian mediators (BRCA1, 53BP1, MDC1/NFBD1) in DNA damage responses, and reconstruction of checkpoint signaling cascades using purified yeast checkpoint proteins.
  • In collaboration with several other breast cancer researchers, we are analyzing molecular differences of ductal carcinoma in situ that are associated with aggressive biological properties leading to invasion or eventual relapse.
  • In collaboration with Ruth Halaban, Mario Sznol, and other members of the Yale Skin SPORE, we are evaluating the potential to predict melanoma treatment responses through deep analysis of signal transduction processes and genetic changes.