Targeting centrosome‐mitotic kinases as a novel therapeutic approach against breast cancers in Hispanic/Latinas.

Ponce School Of Medicine, Ponce PR

Investigators

Linked publications & trials

Abstract

Triple-negative breast cancer (ER-PR- and Her2- or TNBC) is the most aggressive breast cancer subtype. Incidence and mortality from TNBCs are higher in individuals with significant African genomic ancestry in our catchment areas (Tampa and Puerto Rico). TNBCs are more likely to be detected at higher stages and grades. Centrosome amplification (CA)-driven mitotic dysfunction leading to chromosome instability (CIN) and aneuploidy may also contribute to metastasis and poor clinical outcomes of these TNBC patients. The Co-PIs published that the centrosome/mitotic kinases TTK and NEK2 generate CA/CIN and that TTK and NEK2 drive the epithelial to mesenchymal transition (EMT). Preliminary data indicate that TTK and NEK2 are dysregulated in TNBCs and differentially expressed in patients from different ancestral genomic backgrounds. Also, by using a novel NCI-BMAP3 region breast cancer tissue microarray (TMA) containing samples from breast cancer patients from our catchment area, the Co-PIs found that TTK is overexpressed in TNBC and TTK correlates with EMT in TNBC. Inactivating TTK restored Rb in TNBC cells, suggesting it can restore Palbociclib responses. Co-inactivating TTK in TNBC cells reduced the levels of centrosome/mitotic regulators and EMT markers, and co-inactivating TTK/NEK2 significantly reduced the migration and invasion of TNBC. The study team hypothesizes that TTK and NEK2 dysregulation in breast cancer patients from our catchment areas contributes to their poor survival outcomes by driving cancer cell survival and early metastasis. To test this hypothesis, the team proposes the following Specific Aims: (1) Investigating signaling pathways linking mitotic kinases to early metastasis and poor prognosis of in patients from different ancestral genomic backgrounds with breast cancer. The team will determine if expression signatures and copy number variations correlate with the expression of mitotic kinases with EMT markers, and survival outcomes, using RNA and DNA seq done by the ORIEN consortium and a novel TMA. (2) To address how co-inactivation of mitotic kinases suppresses the mesenchymal state, metastasis, and restores Palbociclib responses in TNBC cells. This will be addressed by single and combinatorial inhibition of TTK, NEK2, and TBK1 in primary cell lines and PDX models of TNBC from patients with breast cancer. Results from the proposed experiments will identify actionable targets (TTK, NEK2, and other novel kinases found in Aim 1) against the aggressive growth and early metastatic progression in patients with TNBC.