Ralf Landgraf, Ph.D.
Associate Professor of Biochemistry & Molecular Biology
Description of Research
The deregulation of ERBB (HER) receptor tyrosine kinases (EGFR, ERBB2, ERBB3 and ERBB4) is a widespread phenomenon in a broad range of cancers, but ERBB signaling has the potential to elicit cell proliferation, differentiation, migration and programmed cell death, depending on the signaling context. Approaches based on the direct inhibition of overactive or overexpressed ERBB receptors by kinase inhibitors or antibodies have validated ERBB receptors as drug targets in cancer therapy, but the limitations of these approaches have also highlighted our incomplete understanding of their modes of regulation, and indeed the control of cell surface receptors in general. A more detailed mechanistic understanding of ERBB receptor control will not merely “fill in the blanks” in our mechanistic models and better explain so far non understood modes of action and limitations of existing treatments, but it will open up fundamentally new levels of regulatory control for targeted drug design. A special focus of our work is the signaling through the ERBB2/HER2 and ERBB3/HER3 receptors.
Redirecting the outcome of ERBB signaling through receptor targeted intervention: We found that ERBB2, which is overexpressed in many cancers, in particular in many breast cancers, has receptor-intrinsic control mechanisms that actively suppress the formation of stable and active dimers. During overexpression, this gives rise to high levels of activated receptors but not elevated states of activation. Mutants of ERBB2 that are defective in this level of control can generate cytotoxic signals. Our studies also indicate that a similar shift in the outcome of signal interpretation can be achieved by forcing ERBB2 into an unnatural signaling microenvironment and into a different signaling context relative to ERBB3. We are studying the precise molecular control elements with the goal of manipulating overexpressed ERBB2 receptors through receptor targeted macromolecules, such as aptamers, to enforce cell death promoting signals.
Dissecting and influencing the membrane microenvironment of ERBB receptors: The immediate microenvironment of ERBB receptors plays a significant and poorly understood role in the control of signaling outcomes by placing receptors into specific lipid environments that alters their intrinsic activity and availability of signaling partners. These highly dynamic microenvironments and signaling platforms also represents the interface of receptor signaling and complex lipid metabolism. While an intersection of both areas has been implied in several clinical studies, implying a connection between the lipid environment or composition and disease progression or emergence of resistance phenomena, we currently lack a mechanistic framework to explain and exploit this interplay. In its initial phase, this work focuses on differences in the microenvironment of ERBB2 and ERBB3 and the role that the perturbations of the lipid profile may have on the modulation of “normal” signaling and drug resistance phenomena. Long-range goals include the identification of the best points for therapeutic intervention to shift signaling outcomes or suppress resistance.
Identification of receptor specific interaction partners during receptor maturation: While factors that target the catalytic activity and elevated level of mature and overexpressed ERBB2 have shown great promise in treatment, it is becoming increasingly clear that its dominant signaling partner, the kinase dead ERBB3 receptor plays a key role in several mechanism of cancer cell evasion from targeted therapy, such as ERBB directed kinase inhibitors. This is in large part due to its strong ability to activate the PI3K/Akt pro-survival signaling pathway. Much of this adaptation occurs at the level of posttranslational control.
- Development and evaluation of ERBB3 directed aptamers that inhibit ERBB2/ERBB3 signaling in cancer cells
- Discovery and dissection of higher order association behavior of ERBB3 receptors, and the role of the modulation of this additional level of control in signal attenuation
- Discovery that ERBB2, overexpressed in breast cancer cells, is not at a state of uncontrolled activation as previously thought. The specific activity of overexpressed ERBB2 is instead maintained within narrow boundaries by receptor intrinsic control mechanisms that ensure growth-promoting outcomes.
- Development of aptamers as live-cell photo cross-linking probes to evaluate the microenvironment of endogenous ERBB receptors in cancer cells
Selected Cancer-Related Publications
Collaborating in the Multidisciplinary Research Program(s):