Ceritinib is a novel triple negative breast cancer therapeutic agent

Abstract

Background Triple-negative breast cancers (TNBCs) are clinically aggressive subtypes of breast cancer. TNBC is difficult to treat with targeted agents due to the lack of commonly targeted therapies within this subtype. Androgen receptor (AR) has been detected in 12–55% of TNBCs. AR stimulates breast tumor growth in the absence of estrogen receptor (ER), and it has become an emerging molecular target in TNBC treatment. Methods Ceritinib is a small molecule inhibitor of tyrosine kinase and it is used in the therapy of non-small lung cancer patients. Enzalutamide is a small molecule compound targeting the androgen receptor and it is used to treat prostate cancer. Combination therapy of these drugs were investigated using AR positive breast cancer mouse xenograft models. Also, combination treatment of ceritinib and paclitaxel investigated using AR− and AR low mouse xenograft and patient derived xenograft models. Results We screened 133 FDA approved drugs that have a therapeutic effect of AR+ TNBC cells. From the screen, we identified two drugs, ceritinib and crizotinib. Since ceritinib has a well- defined role in androgen independent AR signaling pathways, we further investigated the effect of ceritinib. Ceritinib treatment inhibited RTK/ACK/AR pathway and other downstream pathways in AR+ TNBC cells. The combination of ceritinib and enzalutamide showed a robust inhibitory effect on cell growth of AR+ TNBC cells in vitro and in vivo. Interestingly Ceritinib inhibits FAK-YB-1 signaling pathway that leads to paclitaxel resistance in all types of TNBC cells. The combination of paclitaxel and ceritinib showed drastic inhibition of tumor growth compared to a single drug alone. Conclusions To improve the response of AR antagonist in AR positive TNBC, we designed a novel combinational strategy comprised of enzalutamide and ceritinib to treat AR+ TNBC tumors through the dual blockade of androgen-dependent and androgen-independent AR signaling pathways. Furthermore, we introduced a novel therapeutic combination of ceritinib and paclitaxel for AR negative or AR-low TNBCs and this combination inhibited tumor growth to a great extent. All agents used in our study are FDA-approved, and thus the proposed combination therapy will likely be useful in the clinic.

Integrated single-cell and bulk RNA sequencing analysis identifies the predictive signature for prognosis and neoadjuvant chemotherapy responses in breast cancer

“…Among them AR stimulates breast tumor growth in the absence of estrogen receptor, making it an emerging molecular target in the treatment of triple-negative BC [38]. TDong, S et.al designed a novel combination therapy, consisting of enzalutamide and ceritinib, to treat TNBC tumors by dual blockade of androgen-dependent and androgen-independent AR signaling pathways [39]. The ability of CIRBP to promote cancer and in ammation is attributed to its ability to bind and post-transcriptionally regulate mRNA [40,41].…”

Receptor tyrosine kinases: biological functions and anticancer targeted therapy

“…Examples of second-generation TKIs are lapatinib, 252 axitinib, 253 afatinib, 254 dacomitinib, 255 and ceritinib. 256 Third-generation TKIs, such as osimertinib, loratinib, and others, are more selective, have superior therapeutic effects, and are less toxic compared with the first two generations. 257,258 RTKs are important signaling targets in vivo, and thus there are numerous therapeutic drugs specifically designed to target them.…”

“…However, resistance to these TKIs, kinase pathway crossover, and compensatory mechanisms have led to the development of second‐generation TKIs with more diverse targets. Examples of second‐generation TKIs are lapatinib, 252 axitinib, 253 afatinib, 254 dacomitinib, 255 and ceritinib 256 . Third‐generation TKIs, such as osimertinib, loratinib, and others, are more selective, have superior therapeutic effects, and are less toxic compared with the first two generations 257,258 .…”

Six‐Membered Aromatic Nitrogen Heterocyclic Anti‐Tumor Agents: Synthesis and Applications

“…Ceritinib targets anaplastic lymphoma kinase (ALK) and can be orally administered to treat ALK-positive NSCLC, and triple-negative breast cancer (TNBCs) (Scheme 53). [178,179] Ceritinib has been specifically developed to selectively target the ATP binding site, which is highly conserved, in the active form of ALK1. The absorption of oral administration of ceritinib is � 25 %.…”