The interplay of Aurora kinase A, EGFR, and SRC pathways in regulating cancer resistance to targeted therapy

Vladimir Ratushny

doi:10.17918/00008821

The oncogenic kinase SRC, the mitotic regulator Aurora kinase A (AURKA), and the receptor tyrosine kinase epidermal growth factor receptor (EGFR) have each been shown to be involved in cancer development and progression. Increased activity of SRC promotes tumor invasion and metastasis, while overexpression of AURKA drives tumor aneuploidy and chromosomal instability. These actions nominate SRC and AURKA as valuable therapeutic targets for cancer and recently developed inhibitors for SRC and AURKA are at various stages of preclinical and clinical development. Therapeutic inhibitors of EGFR have shown limited success in the clinic because of innate or acquired resistance to these EGFR-targeted drugs, likely to occur through compensatory activation of cancer-promoting effectors downstream of EGFR. We nominated AURKA as a possible resistance mediator to EGFR inhibitors by conducting a small interfering RNA (siRNA) screening of a targeted siRNA library of EGFR interactors. We showed that inhibitors of EGFR synergize with inhibitors of Aurora kinase A to reduce colorectal and squamous cell carcinoma cell line proliferation, colony growth in soft agar, cell motility, increase cell death, and decrease tumor growth in an in vivo xenograft model. Dual inhibition of AURKA and EGFR significantly reduced the activity of SRC and other SRC-family kinases, nominating the SRC signaling pathway as a potential functional determinant of this drug synergy. There are many known cross-connections between the signaling networks of SRC and EGFR. These observations, coupled with the knowledge that SRC and AURKA share a common interaction partner, NEDD9, suggested that a potentially significant functional interaction between SRC and AURKA might exist. Investigating this possibility, we demonstrated a potent synergy between inhibitors of AURKA and inhibitors of SRC in multiple ovarian and colorectal cancer cell lines but not in normal ovarian epithelial cell lines. Combination of AURKA and SRC inhibitors selectively killed cancer cells that have undergone aberrant mitosis, and is associated with a post-mitotic reattachment defect. Combined inhibition of AURKA and SRC potentiates dasatinib-dependent SRC inactivation. Interestingly, we also observed a physical interaction and mutual cross-phosphorylation between SRC and AURKA, in vitro, that enhance SRC kinase activity. Together, these findings provide a scientific rationale for combining either EGFR or SRC inhibitors with inhibitors of AURKA in the clinic.

The interplay of Aurora kinase A, EGFR, and SRC pathways in regulating cancer resistance to targeted therapy

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The interplay of Aurora kinase A, EGFR, and SRC pathways in regulating cancer resistance to targeted therapy

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