Knockdown of CD24 May Enhance Efficacy of Targeted Agents in HER2-Positive Breast Cancer

Article

Therapeutic targeting of CD24 may enhance the efficacy of targeted agents, such as trastuzumab and lapatinib, in treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer, according to a team of researchers led by Mari Hosonaga, MD, of the Department of Breast Oncology, Tokyo Medical University Hospital, Japan.

Therapeutic targeting of CD24 may enhance the efficacy of targeted agents, such as trastuzumab and lapatinib, in treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer, according to a team of researchers led by Mari Hosonaga, MD, of the Department of Breast Oncology, Tokyo Medical University Hospital, Japan.

The investigators noted that although combined therapy using a targeted agent with adjuvant chemotherapy improves survival rates in early-stage HER2-overexpressing breast cancer, approximately 15% of patients relapse, and more than 70% of patients with HER2-positive metastatic breast cancer show resistance to HER2-targeted therapy within 1 year. “Indicators that identify such resistant tumors are thus needed to optimize treatment strategies,” they explained in a report published in the July issue of Cancer Science.

Although CD24 is understood to be a marker of differentiated normal mammary epithelial cells, overexpression of the gene is associated with a poor prognosis in breast cancer. Because HER2-positive breast cancer has a predominantly CD24-positive status, “we wondered whether co-expression of CD24 with HER2 might be associated with therapeutic resistance of HER2-positive cells.”

To investigate the relevance of CD24 expression in HER2-positive breast cancer, they established HER2-expressing cell lines by introducing an expression vector for HER2 into MDA-MB-231-Luc, a human breast cancer cell line that is triple-negative for the estrogen receptor, the progesterone receptor and HER2, and which has been engineered to express luciferase. Two lines of 231-Luc cells were obtained and immunoblot analysis was used to assess expression of HER2 and activation of HER2 signaling. Phosphorylation levels of HER2 and Akt increased in a manner dependent on the proportion of HER2-positive cells, whereas the phosphorylation of extracellular-signal-regulated kinase (Erk) 1⁄2 was not affected by ectopic expression of HER2.

“All our data suggest that HER2-positive cells have advantages in survival under the co-expression of CD24 through the phosphorylation of Akt,” the investigators reported. “In other words, HER2+/CD24+ cells might be selected with an advantage in growth and survival.”

Finally, the authors examined whether knockdown of CD24 might increase the sensitivity of breast cancer cells to HER2-targeted therapy. “Treatment of CD24-depleted or control BT-474 cells with lapatinib, a dual tyrosine kinase inhibitor for both the epidermal growth factor receptor and HER2, revealed that knockdown of CD24, indeed, enhanced the antiproliferative and death-promoting effects of lapatinib,” they reported. They also found that knockdown of CD24 increased the sensitivity of lapatinib-resistent cells to the antiproliferative and death-promoting effects of lapatinib. “These data thus suggest that expression of CD24 supports HER2-dependent cancer cell survival.

“Our results indicate that CD24 plays an important role in regulating HER2-initiated survival signaling in breast cancer cells,” the investigators concluded. “We found a positive association between HER2 and CD24 expression, and that expression of CD24 supports the HER2-PI3K-Akt signaling pathway in HER2-positive breast cancer cells. Given that depletion of CD24 increased the size of the HER2-negative cell subpopulation and suppressed Akt phosphorylation, we suggest that CD24 positively regulates HER2-Akt signaling and thereby promotes resistance to HER2-targeted therapy and consequent tumor progression. Therapeutic targeting of CD24 might thus be expected to enhance the efficacy of HER2-targeted agents.”

 

Recent Videos
Kelley A. Rone, DNP, RN, AGNP-c, highlights the importance of having end-of-life discussions early in a patient’s cancer treatment course.
Patients treated with BCMA-directed immunotherapies for myeloma may experience susceptibility to severe infections following treatment.
4 KOLs are featured in this series.
4 KOLs are featured in this series.
4 KOLs are featured in this series.
4 KOLs are featured in this series.
4 KOLs are featured in this series
BCMA testing tracks clinical changes faster without the need for marker expression vs monoclonal immunoglobulin, a conventional multiple myeloma marker.
Related Content