In vitro studies using DNA barcoded cell-lines demonstrated that resistance to CDK4/6 inhibitors is likely due to the expansion of pre-existing resistant clones, suggesting that targeting resistance upfront could delay the acquisition of clinical resistance.
Multiple mechanisms of acquired resistance to CDK4/6 inhibitors have been identified in clinical and pre-clinical studies . It remains unknown if these mechanisms are pre-existing or acquired during treatment. In addition, the role of ESR1 mutations in resistance to CDK4/6 inhibitors (plus endocrine therapy) is largely unknown, as well as if the mechanisms of resistance to different CDK4/6 inhibitors are disparate.
To get more insight, Dr Cristina Guarducci (Dana-Farber Cancer Institute, MA, USA) studied the clonal dynamics and mechanisms of resistance in vitro using a DNA barcoded, doxycycline-inducible ERS1-mutant MCF7 cell line . These cells express the Y537S ERS1-mutated oestrogen receptor (on top of the wildtype receptor) when treated with doxycycline. Cellular barcoding is a technique in which individual cells are labelled with unique nucleic acid sequences, termed barcodes, so that they can be tracked through space and time .
Cells with or without a mutated oestrogen receptor were treated – in triplicates – with escalating doses of palbociclib or abemaciclib until resistance. Clustering of identical barcodes in the resistant cells indicated that resistance to palbociclib was associated with the selection of pre-existing subclones. In addition, expression of the mutant oestrogen receptor was associated with the selection of different palbociclib-resistant subclones. ESR1 mutation was also associated with an earlier and more heterogeneous clonal selection compared with the wildtype receptor. Resistance to abemaciclib was also associated with the selection of pre-existing subclones. However, in abemaciclib-resistant cells, oestrogen-receptor wildtype cells and oestrogen-receptor mutant cells had a high number of overlapping selected clones. Again, ESR1 mutation was associated with an earlier – but not more heterogenous – selection of subclones.
The barcodes enriched in palbociclib-resistant and abemaciclib-resistant cells were different. This difference was more pronounced in the setting of oestrogen-receptor wildtype cells compared with oestrogen-receptor mutated cells. Functional studies showed that palbociclib-resistant cells retained sensitivity to abemaciclib, while abemaciclib-resistant cells were cross-resistant to palbociclib.
“Resistance to CDK4/6 inhibitors is likely due to the expansion of pre-existing resistant clones, suggesting that targeting resistance upfront could delay the acquisition of clinical resistance. The clonal selection during the acquisition of resistance to palbociclib and abemaciclib is different, highlighting the differences between these 2 CDK4/6 inhibitors,” concluded Dr Guarducci.
- Álvarez-Fernández M, Malumbres M. Cancer Cell. 2020;37:514–529.
- Guarducci C, et al. Clonal evolution and mechanisms of acquired resistance to CDK4/6 inhibitors in ER-WT and ER-Mutant breast cancer. Abstract GS3-07, SABCS 2022, 06–10 December, San Antonio, TX, USA.
- Kebschull JM, Zador AM. Nat Methods. 2018;15:871–879.
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Table of Contents: SABCS 2022
Letter from the Editor
Racial disparity in the tumour microenvironment
Chemo-endocrine therapy worse for cognition than endocrine therapy alone
Early-Stage Breast Cancer
Anti-PD-1/anti-LAG-3 combination highly effective in HER2-negative breast cancer
MammaPrint test predictive for benefit of extended endocrine therapy
HR-positive/HER2-positive Breast Cancer: Trastuzumab-Deruxtecan
Trastuzumab deruxtecan effective in both second-line and neoadjuvant setting
HR-positive/HER2-negative Advanced Metastatic Breast Cancer
Benefit of adjuvant abemaciclib continues to deepen at longer follow-up
First-line ribociclib plus endocrine therapy outperforms combination chemotherapy
Treatment options beyond CDK4/6 inhibition
Triple-Negative Breast Cancer
Baseline CTC count can guide first-line treatment in HR-positive/HER-negative metastatic breast cancer
ZNF689 deficiency promotes intratumour heterogeneity and resistance to immune checkpoint blockade in TNBC
Oestradiol represses anti-tumoural immune response to promote progression of brain metastases
Basic and Translational Research
Resistance to CDK4/6 inhibitors is likely due to expansion of pre-existing resistant clones
Germline pathogenic variants for breast cancer also increase contralateral breast cancer risk
Low-dose tamoxifen still prevents recurrence from non-invasive breast cancer
Endocrine interruption to pursue pregnancy does not impact short-term disease in breast cancer