ACK1 activation in multiple subtypes of breast cancers

Immunohistochemical (IHC) analysis revealed a moderate to strong ACK1 activation in 58% of ER+/PR+, 70% of HER2+, and 47% of TNBC breast cancer samples (Figure 1).

ACK1/TNK2 gene amplified in 30% of metastatic breast cancers

cBioPortal reveals that 30% of metastatic breast cancer exhibited ACK1/TNK2 gene amplification, indicating that the gene amplification as the major cause of the ACK1 activation in breast cancers (Figure 2). The ACK1 gene amplification was seen in 20% of ER+, 11% of ER+/PR+, 13% of HER2+, and 9% of TNBCs (Figure 2). Overall, a significant proportion of four distinct subtypes of breast cancers exhibit ACK1 activation, which is independent of their hormone receptor status.

ACK1 promotes Palbociclib resistance

ACK1 epigenetically regulates expression of cell cycle genes, CCNB1, CCNB2 and CDC20. Pharmacological inhibition of ACK1 using its inhibitor, (R)-9b dampened CCNB1, CCNB2 and CDC20 expression, causing G2/M arrest, culminating in regression of palbociclib-resistant breast tumor growth.  Thus, (R)-9b could be a novel therapeutic option for the breast cancer patients those have developed resistance to CDK4/6 inhibitors.

ACK1 as a new therapeutic target in TNBCs

About 15-20% of all breast cancers do not express estrogen, progesterone or HER2 receptor and classified as triple negative breast cancers (TNBC). These tumors are difficult to treat due to the lack of actionable target. We have uncovered that ACK1 is amplified and activated in TNBCs. Further, we show that genetic or pharmacological loss of ACK1 activity by its inhibitor (R)-9b can suppress breast tumor proliferation (Figure 3).

These data suggests that (R)-9b could be a new therapeutic strategy for breast cancers.

ACK1/TNK2 activation and gene amplification in Breast Cancers

Figure 1. ACK1 activation (phosphorylation) in four major subtypes of breast cancers
Figure 2. ACK1/TNK2 gene amplification in four major subtypes of breast cancers

ACK1 inhibitor sensitizes TNBCs

Figure 3. TNBC cell lines were treated with ACK1 inhibitor (R)-9b and pY176-AKT levels were assessed. C. Cells were treated with (R)-9b and the number of viable cells were counted by trypan blue exclusion assay.