bims-cyhorp 2022-02-20 papers

Issue of 2022–02–20
three papers selected by
Piotr Okupski,

Eur J Cancer. 2022 Feb 13. pii: S0959-8049(22)00002-8. [Epub ahead of print]164 39-51

Serum thymidine kinase activity in patients with hormone receptor-positive and HER2-negative metastatic breast cancer treated with palbociclib and fulvestrant.

International Breast Cancer Study Group

BACKGROUND: Biomarkers for cyclin-dependent kinase 4/6 inhibitors, such as palbociclib, for patients with hormone receptor-positive/HER2-negative metastatic breast cancer are lacking. Thymidine kinase is a proliferation marker downstream of the cyclin-dependent kinase 4/6 pathway. We prospectively investigated the prognostic role of serum thymidine kinase activity (sTKa), in patients treated with Palbociclib + fulvestrant.
PATIENTS AND METHODS: PYTHIA was a phase II, single-arm, multicentre, trial that enrolled 124 post-menopausal women with endocrine-resistant hormone receptor-positive/HER2-negative metastatic breast cancer. Serum samples were collected pre-treatment (pre-trt; n = 122), at day 15 of cycle 1 (D15; n = 108), during the one week-off palbociclib before initiating cycle 2 (D28; n = 108) and at end of treatment (n = 76). sTKa was determined centrally using Divitum®, a refined ELISA-based assay with a limit of detection of 20 Divitum Units (Du)/L. The primary study endpoint was progression-free survival, assessed for its association with pre- and on-treatment sTKa.
RESULTS: Data from 122 women were analysed. Pre-treatment sTKa was not associated with clinical characteristics and moderately correlated with tissue Ki-67. Palbociclib + fulvestrant markedly suppressed sTKa levels at D15, with 83% of patients recording levels below limit of detection. At D28, sTKa showed a rebound in 60% of patients. At each timepoint, higher sTKa was associated with shorter progression-free survival (each p < 0.001), with the strongest effect at D15.
CONCLUSIONS: STKa is an independent prognostic biomarker in patients treated with palbociclib. High pre-treatment sTKa and its incomplete suppression during treatment may identify patients with poorer prognosis and primary resistance. This warrants validation in prospective comparative trials. CLINICALTRIALS.
GOV IDENTIFIER: NCT02536742; EudraCT 2014-005387-15.

Keywords: Breast cancer; Fulvestrant; Palbociclib; Prognostic factors; Serum markers; Thymidine kinase

DOI: https://doi.org/10.1016/j.ejca.2021.12.030

EMBO J. 2022 Feb 14. e110764

Cells on lockdown: long-term consequences of CDK4/6 inhibition.

Alexis R Barr, Sarah E McClelland.

Inhibition of cyclin-dependent kinases Cdk4/6 is emerging as a useful anti-proliferative chemotherapy, but it remains unclear how durable inhibition of cancer cell proliferation is achieved to promote a long-lasting response in patients, or how toxicity is limited to cancer cells with minimal side effects. Two recent papers in The EMBO Journal investigating senescence induction following prolonged Cdk4/6 inhibitor treatment now reveal important insights into ways to increase anti-tumour effects of Cdk4/6 inhibition and to reduce therapy-induced side effects of senescence induction.

DOI: https://doi.org/10.15252/embj.2022110764

Molecules. 2022 Jan 27. pii: 880. [Epub ahead of print]27(3):

Conjugation of Palbociclib with MHI-148 Has an Increased Cytotoxic Effect for Breast Cancer Cells and an Altered Mechanism of Action.

Peter Jaein Choi, Petr Tomek, Moana Tercel, Jóhannes Reynisson, Thomas In Hyeup Park, Elizabeth Alexandra Cooper, William Alexander Denny, Jiney Jose, Euphemia Leung.

The CDK4/6 inhibitor palbociclib, combined with endocrine therapy, has been shown to be effective in postmenopausal women with estrogen receptor-positive, HER2-negative advanced or metastatic breast cancer. However, palbociclib is not as effective in the highly aggressive, triple-negative breast cancer that lacks sensitivity to chemotherapy or endocrine therapy. We hypothesized that conjugation of the near-infrared dye MHI-148 with palbociclib can produce a potential theranostic in triple-negative, as well as estrogen receptor-positive, breast cancer cells. In our study, the conjugate was found to have enhanced activity in all mammalian cell lines tested in vitro. However, the conjugate was cytotoxic and did not induce G1 cell cycle arrest in breast cancer cells, suggesting its mechanism of action differs from the parent compound palbociclib. The study highlights the importance of investigating the mechanism of conjugates of near-infrared dyes to therapeutic compounds, as conjugation can potentially result in a change of mechanism or target, with an enhanced cytotoxic effect in this case.

Keywords: CDK4/6 inhibitor palbociclib; MHI-148; breast cancer; cell cycle arrest; near-infrared fluorescent (NIRF)

DOI: https://doi.org/10.3390/molecules27030880