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William J. Gradishar, MD, FACP, FASCO
William J. Gradishar, MD, FACP, FASCO
Posted: Monday, August 8, 2022
Dual blockade of androgen-independent and androgen-dependent androgen receptor pathways may reduce the growth of androgen receptor (AR)-positive triple-negative breast cancer, according to Suresh K. Alahari, PhD, of Louisiana State University (LSU) Health School of Medicine, New Orleans, and colleagues. In fact, the tyrosine kinase inhibitor ceritinib reduced AR-positive tumor growth significantly when combined with the androgen receptor antagonist enzalutamide, and ceritinib plus paclitaxel slowed the growth of AR-negative or AR-low tumors. The findings of this study were published in the journal Molecular Cancer.
“The combination of paclitaxel and ceritinib showed drastic inhibition of tumor growth compared to a single drug alone,” Dr. Alahari commented in an LSU press release. “All agents used in our study are FDA-approved, and thus the proposed combination therapy will likely be useful in the clinic.”
A total of 133 U.S. Food and Drug Administration (FDA)-approved drugs were screened, and ceritinib was identified as having potential therapeutic effects for AR-positive breast cancer cells. The impact of ceritinib on downstream signaling cascades was examined using tumor cell culture lines. Further, xenographs were derived from an AR-positive breast cancer mouse model and from one woman with triple-negative breast cancer following mastectomy of a metastatic lymph node. Ceritinib alone or in combination with either enzalutamide or paclitaxel was administered to xenograft mice once tumors had reached a size of approximately 100 mm3.
Ceritinib administration to AR-positive tumor cells was found to inhibit the RTK/ACK/AR pathway, and tumor cell growth was significantly reduced in AR-positive tumor cell cultures and xenograft mice following ceritinib/enzalutamide administration. Ceritinib also was found to reduce activation of the FAK–YB-1 signaling pathway, which has been associated with paclitaxel resistance. The combination of ceritinib and paclitaxel slowed the growth of AR-negative and AR-low triple-negative breast cancer models, significantly more so than either drug alone.
Disclosure: The study authors reported no conflicts of interest.
