“EGFR and HER2 in cancer progression and therapy”
Professor Yosef Yarden, Weizmann Institute of Science, Israel
Growth factors, along with adhesion and other molecules, play critical roles in the invasive cell growth taking place in the developing embryo. Invasive growth rarely occurs in adulthood, but malignancy often harnesses growth factors, or their downstream signaling pathways, to enhance tumor aggressiveness and metastasis. The keys for understanding growth factor action in cancer are surface receptors: a group of transmembrane glycoproteins whose cytoplasmic tyrosine kinase function is stimulated upon growth factor binding to the extracellular receptor’s part, and induction of dimer formation. An example is provided by the ErbB family of receptor tyrosine kinases (RTKs), which bind a large family of growth factors sharing an epidermal growth factor- (EGF-) like domain. These receptors instigate a variety of intracellular pathways. The generic pathway entails a cascade of cytoplasmic proteins culminating in transcriptional regulation. Self-production of specific growth factors, expression of mutant forms of ErbB-1/EGFR or overexpression of either ErbB-1 or ErbB-2/HER2 characterizes a large variety of tumors of epithelial and glial origin. Moreover, two classes of pharmacological drugs, namely: monoclonal anti-receptor antibodies and low molecular weight tyrosine kinase inhibitors, effectively intercept growth factor signaling in clinical settings.
ErbB-2/HER2 is one of the most potent oncoproteins, but unlike other family members, it binds no soluble growth factor. Likewise, ErbB-3 binds several growth factors, but unlike its family members the intrinsic kinase domain of ErbB-3 is catalytically inactive. For these and other reasons, signaling by ErbB and other RTK families is best described in terms of highly interconnected, layered signaling networks. The fail-safe (robust) ability of the ErbB network to decode and integrate extracellular signals is attributed to its modular structure, as well as to a dense array of feedback regulatory loops, collectively establishing system control.
The research of professor Yarden’s group within the realm of system control within the ErbB family has over the past few years established several general groups of regulatory mechanisms, which are described below with an emphasis on their collapse in human cancer.
Mechanisms of EGF-induced metastasis
The epidermal growth factor receptor (EGFR) is involved in various cellular processes, including proliferation and motility, and its constitutive activation contributes to the transition from the primary tumor site into an invasive state leading to metastases. The ability of EGFR-family receptors to spearhead a chemotactic response relevant to tumor metastasis is actively studied in the Yarden laboratory. Because the initiation of motility requires MAPK activation, as well as synthesis of a new set of RNA molecules, the research has been concentrated on specific groups of transcripts. Since metastases are the primary cause of cancer patients’ death, the identification of events that culminate in a robust transition to a motile cellular state is of utmost importance for the understanding of the EGF-induced metastatic process.
Regulation of signal transduction by non-coding RNAs
Regulation of signaling pathways entails feedback and feedforward loops that underlie cellular responses to external stimuli. Deviations from this tight regulation might propel changes that can be pathogenic and lead to the development and progression of cancer, among other diseases. In recent years, non-coding RNAs emerged as critical regulators of gene expression by acting predominantly at the post-transcriptional level. Professor Yarden’s research within the non-coding RNAs domain focuses specifically on microRNAs (miRNAs), circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs) and has over the past few years established their role in signaling networks upon EGF treatment.
Proof-of-concept experimental therapies of cancer and mechanisms of resistance to anti-cancer drugs
The human EGFR-family plays critical roles in tumor progression. As such, several therapies intercepting these receptors have been developed and clinically approved. The Yarden lab has throughout the years successfully developed numerous antibodies targeting the EGFR-family, both receptors and cognate ligands. Currently emerging are also pharmacological strategies able to circumvent resistance and re-sensitize patients to therapeutic treatments. More recently, the research group started focusing upon a feature that might change the landscape of cancer therapy in the near future, namely concurrent delivery of several distinct antibodies. Individual antibodies in such cocktails might share an antigen molecule (homo-combinations), or they might engage distinct, yet complementary antigens (hetero-combinations). As such, Yarden envision a tailor-made strategy for cancer treatment, which combines (or not) chemotherapeutic agents with two or more antibodies.