Anti‐cancer Effects of Dual‐action Inhibitors of Nek2 and EGFR Kinases: Investigation of Synergy

Abstract

While lung cancer is the leading cause of mortality among all cancer types for both men and women, breast cancer dominates cancer diagnosis among women patients. Never in mitosis gene A (NIMA)‐related kinase 2 (Nek2) is a member of NEK family, a Ser/Thr kinase, that is overabundant in both cancer types. Studies from our laboratory have shown that abnormal expression of Nek2 kinase can promote aggressive tumor behavior and metastasis. Nek2 overexpression also drives drug resistance. These tumors also overexpress another key oncogene, epidermal growth factor receptor (EGFR), that has shown to induce cell proliferation, angiogenesis, and tumorigenesis. Hence, concomitant inhibition of Nek2 and EGFR kinases can potentially be a promising therapeutic strategy for both lung and breast cancers. Our goal is to develop anticancer agents that targets inhibition of both Nek2 and EGFR activities. Our hypothesis is such dual‐action inhibitory agents will provide superior efficacy due to a more predictable PK/PD profile in vivo. In this work, we first test our hypothesis that dual inhibition of Nek2 and EGFR kinases by small molecules will indeed yield net signaling output that results in synergistic cancer cell death in A549 (lung) and MDA‐MB‐231 (breast) cells. Using a novel drug‐like pharmacophore identified in our laboratory, we have also developed small molecule inhibitors that inhibits both Nek2 and EGFR activities. We anticipate that these findings will render new opportunities toward development of targeted small molecule therapeutics for both lung and breast cancers.