bims-cyhorp 2021-12-26 papers

Issue of 2021–12–26
six papers selected by
Piotr Okupski,

Breast. 2021 Dec 13. pii: S0960-9776(21)01014-6. [Epub ahead of print]

Integrating CDK4/6 inhibitors in the treatment of patients with early breast cancer.

CDK4/6 inhibitors have an established role in the treatment of hormone receptor positive HER2-negative advanced breast cancer. All studies conducted in metastatic breast cancer showed a benefit in delaying progression when added to standard endocrine therapy, regardless of therapy line, pretreatment, menopausal status, site of metastasis, CDK4/6 inhibitor used and associated endocrine therapy. A benefit in overall survival has also been demonstrated. In early breast cancer, only the MonarchE study has shown an improved invasive disease-free survival with abemaciclib taken for 2 years, whereas the Penelope-B did not meet the primary endpoint and the PALLAS study was terminated early for futility. Studies conducted in the neoadjuvant setting might help to explain the discordant results.

Keywords: CDK4/6 inhibitors; Early setting; Endocrine therapy; Hormone receptor positive breast cancer

DOI: https://doi.org/10.1016/j.breast.2021.12.008

Int J Mol Sci. 2021 Dec 14. pii: 13423. [Epub ahead of print]22(24):

A Search for Cyclin-Dependent Kinase 4/6 Inhibitors by Pharmacophore-Based Virtual Screening, Molecular Docking, and Molecular Dynamic Simulations.

Ni Made Pitri Susanti, Sophi Damayanti, Rahmana Emran Kartasasmita, Daryono Hadi Tjahjono.

The G1 phase of cell cycle progression is regulated by Cyclin-Dependent Kinase 4 (CDK4) as well as Cyclin-Dependent Kinase 6 (CDK6), and the acivities of these enzymes are regulated by the catalytic subunit, cyclin D. Cell cycle control through selective pharmacological inhibition of CDK4/6 has proven to be beneficial in the treatment of estrogen receptor-positive (ER-positive) breast cancer, particularly improving the progression-free survival of patients. Thus, targeting specific inhibition on CDK4/6 is bound to increase therapeutic efficiency. This study aimed to obtain CDK4/6 inhibitors through a pharmacophore-based virtual screening of the ZINC15 purchasable compound database using the in silico method. The pharmacophore model was designed based on the FDA-approved cdk4/6 inhibitor structures, and molecular docking was performed to further screen the hit compounds obtained. A total of eight compounds were selected based on docking results and interactions with CDK4 and CDK6, using palbociclib as the reference drug. According to the results, the compounds of ZINC585292724 and ZINC585291674 were the best compounds based on free binding energy, as well as hydrogen bond stability, and, therefore, exhibit potential as starting points in the development of CDK4/6 inhibitors.

Keywords: CDK4; CDK6; cell cycle; molecular docking; molecular dynamic; pharmacophore; virtual screening

DOI: https://doi.org/10.3390/ijms222413423

Cancers (Basel). 2021 Dec 16. pii: 6314. [Epub ahead of print]13(24):

Ribociclib Induces Broad Chemotherapy Resistance and EGFR Dependency in ESR1 Wildtype and Mutant Breast Cancer.

Isabel Mayayo-Peralta, Beatrice Faggion, Liesbeth Hoekman, Ben Morris, Cor Lieftink, Isabella Goldsbrough, Lakjaya Buluwela, Joseph C Siefert, Harm Post, Maarten Altelaar, Roderick Beijersbergen, Simak Ali, Wilbert Zwart, Stefan Prekovic.

While endocrine therapy is highly effective for the treatment of oestrogen receptor-α (ERα)-positive breast cancer, a significant number of patients will eventually experience disease progression and develop treatment-resistant, metastatic cancer. The majority of resistant tumours remain dependent on ERα-action, with activating ESR1 gene mutations occurring in 15-40% of advanced cancers. Therefore, there is an urgent need to discover novel effective therapies that can eradicate cancer cells with aberrant ERα and to understand the cellular response underlying their action. Here, we evaluate the response of MCF7-derived, CRISPR-Cas9-generated cell lines expressing mutant ERα (Y537S) to a large number of drugs. We report sensitivity to numerous clinically approved inhibitors, including CDK4/6 inhibitor ribociclib, which is a standard-of-care therapy in the treatment of metastatic ERα-positive breast cancer and currently under evaluation in the neoadjuvant setting. Ribociclib treatment induces senescence in both wildtype and mutant ERα breast cancer models and leads to a broad-range drug tolerance. Strikingly, viability of cells undergoing ribociclib-induced cellular senescence is maintained via engagement of EGFR signalling, which may be therapeutically exploited in both wildtype and mutant ERα-positive breast cancer. Our study highlights a wide-spread reduction in sensitivity to anti-cancer drugs accompanied with an acquired vulnerability to EGFR inhibitors following CDK4/6 inhibitor treatment.

Keywords: EGFR signalling; breast cancer; cdk4/6 inhibitors; chemotherapy resistance; oestrogen receptor

DOI: https://doi.org/10.3390/cancers13246314

JCI Insight. 2021 Dec 21. pii: e154402. [Epub ahead of print]

RB expression confers sensitivity to CDK4/6 inhibitor-mediated radiosensitization across breast cancer subtypes.

Andrea M Pesch, Nicole H Hirsh, Anna R Michmerhuizen, Kassidy M Jungles, Kari Wilder-Romans, Benjamin C Chandler, Meilan Liu, Lynn M Lerner, Charles A Nino, Connor Ward, Erin F Cobain, Theodore S Lawrence, Lori J Pierce, James M Rae, Corey W Speers.

Standard radiation (RT) therapy does not reliably provide locoregional control for women with multi-node positive and triple-negative (TNBC) breast cancers. We hypothesized that CDK4/6 inhibition (CDK4/6i) would increase the radiosensitivity not only of estrogen receptor positive (ER+) cells, but also TNBC that express retinoblastoma (RB) protein. We found that CDK4/6i radiosensitized RB wild-type TNBC (n=4, rER 1.49 - 2.22), but failed to radiosensitize RB-null TNBC (n=3, rER: 0.84 - 1.00). RB expression predicted response to CDK4/6i + RT (R2=0.84), and radiosensitization was lost in ER+/TNBC cells (rER: 0.88 - 1.13) after RB1 knockdown in isogenic and non-isogenic models. CDK4/6i suppressed homologous recombination (HR) in RB wild-type cells, but not in RB-null cells or isogenic models of RB1 loss; HR competency was rescued with RB re-expression. Radiosensitization was independent of non-homologous end joining and the known effects of CDK4/6i on cell cycle arrest. Mechanistically, RB and RAD51 interact in vitro to promote HR repair. CDK4/6i produced RB-dependent radiosensitization in TNBC xenografts, but not in isogenic RB1-null xenografts. Our data provide the preclinical rationale for a clinical trial expanding the use of CDK4/6i + RT to difficult to control RB-intact breast cancers (including TNBC) and nominate RB status as a predictive biomarker of therapeutic efficacy.

Keywords: Breast cancer; DNA repair; Oncology; Radiation therapy

DOI: https://doi.org/10.1172/jci.insight.154402

Case Rep Oncol. 2021 Sep-Dec;14(3):14(3): 1601-1607

Surgery to Oligometastatic Breast Cancer after Excellent Response to Palbociclib and Letrozole Therapy: Pitfall of Ultrasound Therapeutic Evaluation.

Suzuka Fujii, Shoji Oura, Shinichiro Makimoto.

A 48-year-old woman with regional recurrences of breast cancer in the axillar and supraclavicular regions was referred to our hospital. Under the diagnosis of recurrent luminal breast cancer with a high Ki-67 labeling index of >30% and a disease-free interval of 13 years, the patient began to receive palbociclib, letrozole, and luteinizing hormone-releasing hormone agonist, resulting in marked response of the supraclavicular lesion and stable disease of the axillar lesion on ultrasound (US) evaluation. Positron emission tomography (PET)/computed tomography of the axillar and supraclavicular foci showed high and no avidities before and after treatment, respectively. The unmovable neck lesion became movable with the treatment. The patient, therefore, underwent surgical resection of the 2 metastatic foci to examine the discordant therapeutic efficacy against the 2 metastatic foci on 2 image modalities, that is, US and PET, and to possibly get a cure of the breast cancer oligometastasis. Pathological examination showed marked fibrosis and scant cancer cell residuals with microcalcifications in the neck tumor and massive sarcoid-like reaction with scant cancer cell residuals in the axillary nodes. The residual cancer cells showed estrogen and progesterone receptor positivities, human epidermal growth factor receptor type 2 negativity, and an extremely low Ki-67 labeling index of 2.5%. The patient recovered uneventfully and has continued palbociclib-containing endocrine therapy for 1 year without any recurrences. Breast oncologists should well understand the basic principles of internal echo formation on US and take the presence of sarcoid-like reaction in the cancer cell clusters into consideration on the therapeutic evaluation of metastatic breast cancer.

Keywords: Breast cancer; CDK 4/6 inhibitor; Oligometastasis; Sarcoid-like reaction

DOI: https://doi.org/10.1159/000519567