Mechanisms of Resistance to CDK4/6 Inhibitors in Hormone Receptor-Positive (HR +) Breast Cancer: Spotlight on Convergent CDK6 Upregulation and Immune Signaling

Brett, Jamie O.; Herman, Paige; Mayer, Erica L.; Bardia, Aditya; Wander, Seth A.

doi:10.1007/s12609-022-00461-3

Cited by 1 publication

(1 citation statement)

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“…Acute IFN exposure promotes anti-tumour activity by suppressing Tregs and stimulating tumour antigen presentation, and NK and cytotoxic T cell activity 43 . Historically, IFNs have also shown anti-tumour effects by inducing apoptosis and inhibiting cell cycle progression in BC 44 . In contrast, persistent IFN exposure promotes T-cell exhaustion and is associated with resistance to multiple therapy types including immunotherapy, chemotherapy, radiotherapy, and endocrine therapy [45][46][47][48][49][50] .…”

Section: Discussionmentioning

confidence: 99%

Acquired resistance to CDK4/6 inhibition is associated with dysregulation of multiple pathways including cyclin D-CDK4/6-RB, EGFR/HER, AKT/mTOR and IFN signaling

Spears,

Bathurst,

Liao

et al. 2024

Preprint

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While the use of CDK4/6 inhibitors has significantly improved outcomes for patients with ER+/HER2- tumours, understanding the mechanisms responsible for resistance is essential to identify predictive biomarkers and alternative treatment options after tumour progression. To this end, we developed in-vitro models of acquired resistance to palbociclib and abemaciclib using MCF7 and T47D cell lines. Genomic, transcriptomic, and proteomic analyses were used to identify potential actionable molecular alterations in these models. Results show that acquired resistance was associated with dysregulation of multiple signaling pathways, including cyclin D-CDK4/6-RB, EGFR/HER and AKT/mTORC1. Strikingly, acquired resistance across all cell lines was also associated with an upregulated interferon (IFN) response. Expression of an IFN-based gene signature derived from these models was upregulated in breast cancer cell lines and early-stage tumours intrinsically resistant to CDK4/6i, and thus warrants further clinical evaluation as a predictive biomarker of resistance.

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