Investigating combinatorial ligand addiction provides insights into rational drug combinations in cancer therapy

Abstract

Cancer, the second most common cause of death in the United States, is a collection of diseases caused by uncontrolled cell growth and metastasis. The main treatment for cancer is chemotherapy, which generally kills fast growing cells nonspecifically and has many side effects. A different type of cancer treatment, called targeted therapy, aims to avoid general toxicity by using drugs that block the activity of specific gene products, usually encoded by oncogenes, which have been shown to drive tumor growth. To date, targeted therapies, alone or in combination with chemotherapies, have mainly been successful in rare subsets of patients with tumors addicted to single oncogenes. This has created a rationale to mainly treat patients with an oncogene-addiction (such as those carrying mutated or overexpressed kinases) with targeted therapies like erlotinib and trastuzumab, which inhibit human epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2/ErbB2), respectively. Here, evidence is provided that targeted therapies are also effective in tumors that are dependent on multiple growth factors - a phenomenon that is called combinatorial ligand addiction. Specifically, it is shown that ligands that bind the EGFR family and the hepatocyte growth factor receptor (HGFR/MET) can activate protein kinase B (PKB/ AKT) across a broad set of cancer cell lines, suggesting that ligand signaling is redundant and widespread. It is also shown that ErbB ligands have distinct signaling dynamics and strengths, which provides a rationale for investigating each component of the ErbB signaling network. Using a systematic approach, we found that ErbB3 is an imp01tant therapeutic target even though it is not overexpressed and lacks kinase activity. Furthermore, it is shown that cell lines with and without known oncogene-addiction express autocrine ligands and have improved growth inhibition with drug combinations that include autocrine ligand-blocking antibodies. This research demonstrates that combinatorial ligand addiction creates a new rationale for therapeutic combinations to improve efficacy and prevent resistance in cancer cells that are treated with current targeted drugs.