Characterization of BRCA1-deficient breast cancer cells with acquired resistance to CHK1 inhibitor therapy

Abstract

Breast cancer is the second most lethal form of diagnosed cancer in women today. Women who have inherited mutations in the Breast Cancer Associated 1 (BRCA1) gene have a 70-90% chance of developing breast cancer at some point in their lifetime. These cancers are often highly aggressive with very few treatment options. A previously conducted chemical screen indicated that BRCA1 deficient breast cancer cells express an increased sensitivity to drugs that inhibit the cell cycle protein checkpoint kinase 1 (CHK1). CHK1 inhibitors are used clinically in combination with chemotherapeutics and other DNA damaging agents, but BRCA1 deficient breast cancer cells display sensitivity to these drugs as single agents. This gives CHK1 inhibitors promise as a targeted therapy for BRCA! deficient cancers. However, tumor recurrence and resistance to targeted therapies is a growing issue clinically. The purpose of this study was to analyze how initially sensitive cells change upon acquiring resistance to CHK1 inhibitors, and to begin to elucidate possible mechanisms of resistance. It was shown that the resistant cells display and overall decrease in aggressive characteristics when assessing proliferation, migration, colony formation, and mammosphere formation abilities. Phospho-receptor tyrosine kinase and phospho-kinase arrays revealed several signaling pathways that could be conferring resistance to CHK1 inhibitors in these cells, taken together this study gives insight into how cells can change upon acquiring resistance to CHK1 inhibitors and points towards possible mechanisms of resistance. this knowledge is important to understand how CHK1 inhibitors could dbe used clinically, specifically in treating cancers that result from BRCA1 deficiency.