Cell Signaling in Cancer Biology

Several key signaling pathways control the growth and motility of normal cells, whereas abnormal activation of these pathways often leads to uncontrolled cell growth and motility, cell transformation and cancer development.

Over the last few decades a remarkable progress in the signal transduction field led to identification of signaling pathways and key genes known as ‘oncogenes that activate cell growth or motility in an uncontrolled manner. Similarly, loss of ‘tumor suppressor’ genes can also lead to cancer development and metastasis. Targeting of signaling pathways is a common strategy in cancer therapy, and currently several signalling cascades, including the PI3K/mTOR pathway, JAK/STAT, Ras/Raf/MAPK as well as the EGFR, HER2 and cMet pathways are considered as potential therapeutic targets for different cancers including breast cancer.

The major challenge is to identify critical signaling pathways and intermediate components that contribute to cancer development and/or metastasis and target them by small molecule inhibitors or specific antibodies.  Prof. Sima Lev and her research team are seeking to identify key signaling pathways that contribute to breast cancer development and metastasis, and to understand how these pathways are regulated and communicate with other pathways within a ‘signaling network’.

. Prof. Lev investigates the dynamics and reprogramming of signaling networks in response to drug treatment or gene perturbations, with the aim to understand the underlying mechanisms of drug response and drug resistance.

Studies of Prof. Sima Lev from the Molecular cell biology Department at the Weizmann Institute of Science are focused on signaling pathways triggers by tyrosine kinase receptors (RTKs) activation in particular EGFR, cMet (https://en.wikipedia.org/wiki/C-Met) and AXL

(https://en.wikipedia.org/wiki/AXL_receptor_tyrosine_kinase) and the non-receptor

tyrosine kinases PYK2  and FAK.

 

EGFR, cMet and AXL are considered as potential molecular targets for triple negative breast cancer (TNBC) therapy. These three RTKs transphosphorylate and activate each other, and also share common downstream effectors. Hence, inhibition of one receptor is frequently compensated by signaling through the other two. Resistance to EGFR inhibition, for example, can be overcome by signaling through cMet or AXL receptor, and is attributed, in many cases, to overexpression/amplification of cMet, AXL or their ligands HGF or GAS6 (see picture below). The goal of Prof. Sima Lev studies is to understand the crosstalk signaling of these three receptors and to find efficient strategy to target them as a therapeutic strategy.

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