Novel Cell Cycle Inhibitors Decrease Primary and Metastatic Breast Cancer Growth In Vivo

TL;DR

This study identifies new cell cycle inhibitors that reduce breast cancer growth and metastasis in mice, offering potential new treatments.

Contribution

The study discovers novel CDK-2/9 inhibitors effective against breast cancer in vivo using patient-derived CTCs.

Findings

Five compounds inhibiting CDK-2/9 reduced tumor growth and metastasis in mouse models.

Transcriptome analysis showed altered cell cycle pathways in treated cancer cells.

The compounds demonstrated good tolerability at 15 mg/kg in vivo.

Abstract

Breast cancer is a leading cancer worldwide, with metastasis causing high death rates. Currently, patients with overt metastatic disease are considered incurable. We used patient-derived circulating tumor cells (CTCs) to screen 250 small molecules, identifying five compounds with potential anti-cancer effects. These compounds, which inhibit cyclin-dependent kinase (CDK-2/9), effectively reduced tumor growth and metastasis in mouse breast cancer models. Transcriptome profiling of treated cancer cells revealed alterations in pathways associated with cell cycle regulation, providing mechanistic insights into the anti-cancer effects of the compounds. Altogether, these results contribute to providing new therapeutic tools that could be implemented for the treatment of breast cancer.

Background: Breast cancer is one of the most frequently diagnosed cancers worldwide, with metastasis contributing to high mortality rates. Current treatments for metastatic disease are limited, emphasizing the urgent need for novel therapeutic approaches. Methods: We conducted a small-molecule drug screen utilizing patient-derived circulating tumor cells (CTCs) as a platform to identify potential anti-cancer agents. We used a dye combination and a high-content imaging microscope to evaluate cellular viability upon compound treatment. Among the 250 small molecules tested, potential hits were identified. The efficacy of these compounds was investigated using in vitro and in vivo studies in mouse breast cancer models. Bulk RNA sequencing of treated cancer cells was performed to identify differentially expressed genes, with Gene Ontology enrichment analyses conducted for their functional characterization. Results: Our screen of a 250 small-molecule library led to the identification of five hits, derivatives of meriolins known to display cyclin-dependent kinase (CDK-2/9) inhibitory activity. Subsequent in vitro and in vivo studies validated the efficacy of these compounds in inhibiting cell cycle, tumor growth, and consequently, metastatic colonization in mouse breast cancer models. Treatment with single agents (15 mg/kg) in breast cancer mouse models demonstrated good tolerability in vivo. Transcriptome profiling of treated cancer cells revealed alterations in pathways associated with cell cycle regulation, providing mechanistic insights into the anti-cancer effects of the compounds. Conclusions: By integrating drug screens, transcriptomic analysis, and in vivo validation, our study contributes to the identification of novel promising candidates for the treatment of breast cancer.

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