Since the introduction of chemotherapy in cancer therapy, development of resistance to every new therapeutic
has been the universal experience. The growing understanding of cancer genomics, cancer-associated signal transduction
pathways, and key protein drivers of cancer has enabled cancer biologists and medicinal chemists to develop targeted
molecules to interfere with these pathways to tackle drug resistant cancers. However, to the dismay of oncologists, the
clinical use of many of these tools has once again brought to the forefront the inevitable challenge of drug resistance. It is
now understood that cancer resistance to different therapies involves multiple challenges that encompass the cancer cell itself
as well as host physiology. This review presents small molecule inhibitors and peptides as two therapeutic approaches
in anti-cancer drug development. Resistance to selected samples of these novel therapies is described in the context of cell
autonomous resistance, the contributions of the tumor microenvironment, and germ line factors. For each approach, advantages
and disadvantages are discussed on how to better overcome the inevitable challenge of resistance in cancer treatment.
Keywords: Anti-cancer peptides, drug resistance, small molecule inhibitors, targeted cancer therapy.
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