Targeting the Id1-Kif11 Axis in Triple-Negative Breast Cancer Using Combination Therapy

Abstract

The basic helix-loop-helix (bHLH) transcription factors inhibitor of differentiation 1 (Id1) and inhibitor of differentiation 3 (Id3) (referred to as Id) have an important role in maintaining the cancer stem cell (CSC) phenotype in the triple-negative breast cancer (TNBC) subtype. In this study, we aimed to understand the molecular mechanism underlying Id control of CSC phenotype and exploit it for therapeutic purposes. We used two different TNBC tumor models marked by either Id depletion or Id1 expression in order to identify Id targets using a combinatorial analysis of RNA sequencing and microarray data. Phenotypically, Id protein depletion leads to cell cycle arrest in the G0/G1 phase, which we demonstrate is reversible. In order to understand the molecular underpinning of Id proteins on the cell cycle phenotype, we carried out a large-scale small interfering RNA (siRNA) screen of 61 putative targets identified by using genomic analysis of two Id TNBC tumor models. Kinesin Family Member 11 (Kif11) and Aurora Kinase A (Aurka), which are critical cell cycle regulators, were further validated as Id targets. Interestingly, unlike in Id depletion conditions, Kif11 and Aurka knockdown leads to a G2/M arrest, suggesting a novel Id cell cycle mechanism, which we will explore in further studies. Therapeutic targeting of Kif11 to block the Id1–Kif11 axis was carried out using small molecular inhibitor ispinesib. We finally leveraged our findings to target the Id/Kif11 pathway using the small molecule inhibitor ispinesib in the Id+ CSC results combined with chemotherapy for better response in TNBC subtypes. This work opens up exciting new possibilities of targeting Id targets such as Kif11 in the TNBC subtype, which is currently refractory to chemotherapy. Targeting the Id1–Kif11 molecular pathway in the Id1+ CSCs in combination with chemotherapy and small molecular inhibitor results in more effective debulking of TNBC.

KIF11 Serves as an Independent Prognostic Factor and Therapeutic Target for Patients With Lung Adenocarcinoma

“…These data imply that KIF11 may be a promising therapeutic target for LUAD. It has been reported that KIF11 plays essential roles in G2/M phase transition and cell cycle checkpoints during mitosis, subsequently modulating tumor progression (26,27). Jiang et al found that high KIF11 expression was correlated with triple negative breast cancer (TNBC) and indicated poor diseasefree survival (28).…”

LGG subtypes based on the activity changes of immunologic and hallmark gene sets in cancer

“…It is simply described to be closely related to the tumor microenvironment [15][16][17][18]. AURKA and KIF11 are used as a target in many tumors for targeted therapy, and these genes are also microenvironment constituent genes of tumors [19][20][21][22]. CKD1 has not been studied much in glioma.…”

Transcriptome Profile Analysis of Triple-Negative Breast Cancer Cells in Response to a Novel Cytostatic Tetrahydroisoquinoline Compared to Paclitaxel

“…The ID genes may control cell division by the indirect regulation of processes involving CDKN1A (p21) and CDKN1B (p27) [ 55 ]. In TNBC and other cancers, the ID oncogenic transcripts foster diverse cancer-related events, including EMT, signaling (e.g., EGFR/TGF-beta [ 56 , 57 , 58 , 59 , 60 , 61 ], K-Ras, WNT, STAT3, PI3K/Akt, OCT-4/ID1/NF-kappaB), where ID genes are a target of many anticancer drugs, including vinblastine [ 62 , 63 ]. Drugs such as GM-4-53 that can downregulate IDs are believed to offer therapeutic roles in the attenuation of TNBC progression and other cancers [ 64 , 65 , 66 ], with a capacity to offset chemoresistance associated with various drugs [ 67 , 68 , 69 , 70 , 71 ].…”

“…Regarding the impact of downregulated ID transcripts by both paclitaxel and GM-4-53, these are known to play a direct role in impeding cell division. Several studies seem to suggest that ID1 exerts control over cell cycle and self-renewal capacity of TNBC in vitro and in vivo [ 57 ], with its absence (silencing) leading to G0/G1 cell cycle arrest [ 56 ].…”