Roles of signaling pathways in drug resistance, cancer initiating cells and cancer progression and metastasis

• DOI: 10.1016/j.jbior.2014.09.016
• Publication Date: 2014-10-09T15:22:58Z
• Authors: James A. McCubrey; Stephen L. Abrams; Timothy L. Fitzge...; Lucio Cocco; Alberto M. Martelli; Giuseppe Montalto; Melchiorre Cervello; Aurora Scalisi; Saverio Candido; Massimo Libra; Linda S. Steelman
• Keywords: Male; 0301 basic medicine; EGFR; Targeted therapy; 03 medical and health sciences; Breast cancer; HER2; Neoplasms; Animals; Humans; Neoplasm Metastasis; Cell Proliferation; Cancer stem cells; Therapy resistance; Neoplasm Proteins; 3. Good health; Gene Expression Regulation, Neoplastic; Cell Transformation, Neoplastic; ER; Breast cancer; Cancer stem cells; EGFR; ER; HER2; Hormonal therapy; Targeted therapy; Therapy resistance; Drug Resistance, Neoplasm; EGFR; HER2; BREAST CANCER; ER; CANCER STEM CELLS; TARGETED THERAPY; hormonal therapy; therapy resistance; Female; Hormonal therapy; Signal Transduction

The EGFR/PI3K/PTEN/Akt/mTORC pathway plays prominent roles in malignant transformation, prevention of apoptosis, drug resistance, cancer initiating cells (CICs) and metastasis. The expression of this pathway is frequently altered in breast and other cancers due to mutations at or aberrant expression of: HER2, EGFR1, PIK3CA, and PTEN as well as other oncogenes and tumor suppressor genes. miRs and epigenetic mechanisms of gene regulation are also important events which regulate this pathway. In some breast cancer cases, mutations at certain components of this pathway (e.g., PIK3CA) are associated with a better prognosis than breast cancers lacking these mutations. The expression of this pathway has been associated with CICs and in some cases resistance to therapeutics. We will review the effects of activation of the EGFR/PI3K/PTEN/Akt/mTORC pathway primarily in breast cancer and development of drug resistance. The targeting of this pathway and other interacting pathways will be discussed as well as clinical trials with novel small molecule inhibitors as well as established drugs that are used to treat other diseases. In this manuscript, we will discuss an inducible EGFR model (v-ERB-B:ER) and its effects on cell growth, cell cycle progression, activation of signal transduction pathways, prevention of apoptosis in hematopoietic, breast and prostate cancer models.