ZNF689 deficiency promotes intratumour heterogeneity and resistance to immune checkpoint blockade in TNBC

In triple-negative breast cancer (TNBC), high intratumour heterogeneity (ITH) is associated with a poor response and resistance to immune checkpoint inhibitors. Efavirenz, a reverse-transcriptase inhibitor, showed to improve the efficacy of anti-PD-1 treatment in a mouse model.

TNBC is an aggressive disease characterised by remarkable ITH, which poses a significant therapeutic challenge [1]. However, the key determinants and underlying mechanisms of ITH in TNBC remain to be elucidated. To get more insight into this, both genetic and histologic ITH in 394 TNBC specimens were analysed. Dr Li-Peng Ge (Fudan University Shanghai Cancer Center, China) showed that genetic ITH and histologic ITH are highly correlated [2]. In addition, high ITH (genetic or histologic) is associated with immune-excluding tumour characteristics (low CD8, low tumour-infiltrating lymphocytes).

Results from 4 anti-PD-1-based clinical trials (NCT04613674, NCT04418154, NCT03805399, NCT04129996) demonstrated that high ITH is associated with poor efficacy outcomes. Transcriptomic analysis revealed ZNF689 (a gene coding for Zinc Finger Protein 689) to be involved in ITH. Depletion of ZNF689 in multiple mouse models significantly promoted ITH. In addition, it was shown that ZNF689 eventually facilitated transcriptional silencing and that the reverse-transcriptase inhibitor efavirenz was able to decrease ITH. In a mouse model, efavirenz was able to augment anti-tumour immunity. Consistently, ZNF689 expression positively correlated with favourable prognosis and responsiveness to anti-PD-1 treatment.

Based on these results, Dr Ge concluded that “ZNF689 deficiency promotes ITH and targeting ITH with efavirenz can combat resistance to immune checkpoint inhibition in TNBC.” To further explore the role of ZNF689 and efavirenz in TNBC treatment, the phase 2, open-label, 3-arm Renaissance study (NCT05076682) recently started to test the efficacy and safety of the combination of efavirenz and anti-PD-1 therapy.

1. Marusyk A, et al. Cancer Cell. 2020;37:471–484.
2. Ge L-P, et al. ZNF689 deficiency promotes intratumor heterogeneity and resistance to immune checkpoint blockade in Triple-Negative Breast Cancer. Abstract GS5-05, SABCS 2022, 6–10 December, San Antonio, TX, USA.

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Posted on 1 February, 2023