Abstract
Combination chemotherapy has been a mainstay in cancer treatment for the last 60 years. Although the mechanisms of action and signaling pathways affected by most treatments with single antineoplastic agents might be relatively well understood, most combinations remain poorly understood. This review presents the most common alterations of signaling pathways in response to cytotoxic and targeted anticancer drug treatments, with a discussion of how the knowledge of signaling pathways might support and orient the development of innovative strategies for anticancer combination therapy. The ultimate goal is to highlight possible strategies of chemotherapy combinations based on the signaling pathways associated with the resistance mechanisms against anticancer drugs to maximize the selective induction of cancer cell death. We consider this review an extensive compilation of updated known information on chemotherapy resistance mechanisms to promote new combination therapies to be to discussed and tested.
Highlights
Cancer chemotherapy has evolved greatly since the first clinical trial using nitrogen mustard in1942 [1]
From cytotoxic drugs, the resistance mechanisms of target therapy are mostly specific key alterations in their signaling pathway targets, such as mitogen-activated protein kinase (MAPK) pathway, phosphoinositide 3-kinase pathway (PI3K-AKT-mTOR), epidermal growth factor (EGF), EGF receptor (EGFR), phosphatase and tensin homolog deleted on chromosome 10 (PTEN), insulin-like growth factors (IGFs), key regulators of apoptosis B-cell lymphoma 2 (BCL2) family, fibroblast growth factors (FGFs), and signal transducers and activators of transcription (STATs)
This approach has the limitation that most inhibitors of ATP-binding cassette (ABC) transport and MAPK receptors, PI3K, AKT, and mTOR, showed high toxicity and were not recommended for phase III clinical trial
Summary
Cancer chemotherapy has evolved greatly since the first clinical trial using nitrogen mustard in. In the 1960s, the use of the combination of Vincristine, Amethopterin, 6-Mercaptopurine, and Prednisone (VAMP) for pediatric leukemia markedly changed the stigmatic status of cancer chemotherapy to “curable”, showing drastic increments in remissions and survival. It made evident the superiority of drug combination over monotherapy [2]. Combination therapy aims to hamper cancer cell homeostasis/metabolism at multiple simultaneous targets to improve its therapeutic efficacy, reduce dosage, reduce side effects, and prevent or delay the development of acquired resistance [3]. The information on resistance mechanisms, signaling pathways, and mechanisms of action for cytotoxic and target therapy is summarized in tables and discussed below
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