bims-cyhorp 2022-04-10 papers

Issue of 2022–04–10
seven papers selected by
Piotr Okupski,

Cancer Res. 2022 Apr 08. pii: canres.2428.2021. [Epub ahead of print]

Functional genomic analysis of CDK4 and CDK6 gene dependency across human cancer cell lines.

Zhouwei Zhang, Lior Golomb, Matthew Meyerson.

Cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6) are key cell cycle regulators that are frequently dysregulated in human malignancies. CDK4/6 inhibitors are clinically approved for the treatment of hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer, but improved specificity and reduced toxicity might expand their use to other indications. Through analysis of publicly available genome-wide loss-of-function data combined with single and dual-targeting CRISPR assays, we found differential cell proliferation vulnerability of cell lines to either CDK4 deletion alone, CDK6 deletion alone, combined CDK4/CDK6 deletion, or neither. CDK6 expression was the best single predictor of CDK4 (negatively correlated) and CDK6 (positively correlated) dependencies in the cancer cell lines, with adenocarcinoma cell lines being more sensitive to CDK4 deletion and hematologic and squamous cancer cell lines being more sensitive to CDK6 deletion. RB-E2F signaling was confirmed as a main downstream node of CDK4/6 in these experiments as shown by the survival effects of RB1 deletion. Finally, we show in a subset of cancer cell lines not dependent on CDK4/6 that CDK2-CCNE1 is an important alternative dependency for cell proliferation. Together, our comprehensive data exploration and functional experiments delineate the landscape of pan-cancer CDK4/6 gene dependencies and define unique cancer cell populations that might be sensitive to CDK4-selective or CDK6-selective inhibitors.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-2428

Cancer Res. 2022 Apr 01. 82(7): 1170-1171

Cyclin-Dependent Kinase 4/6 Inhibitors: Is a Noncanonical Substrate the Key Target?

David A Frank.

Cyclin-dependent kinases (CDK), such as CDK4 and CDK6, phosphorylate RB1 to release the transcription factor E2F and drive the transition from G1 to S-phase of the cell cycle. Inhibitors of these kinases thereby block cell-cycle progression and presumably exert their therapeutic effect. While this mechanism is straight forward, several aspects have seemed problematic, not the least of which is that these drugs seem to have therapeutic effects on a relatively small number of human cancers. Tong and colleagues took an open-ended approach to this mechanistic question, and their results raise the possibility that inhibition of phosphorylation of the transcription factor p73 is a key mechanism of action of these drugs. They show that p73 inhibition and the resultant upregulation of the cell surface receptor DR5 are necessary for the anticancer effects of CDK4/6 inhibitors, including enhancement of immune-mediated cell killing, and that therapeutic benefit relies largely on their use in conjunction with other agents. While many questions remain to be answered, these findings demonstrate the importance of keeping an open mind to mechanistic aspects of therapeutic agents already in clinical use and highlight how rigorous mechanistic studies can answer both basic and translational questions. See related article by Tong et al., p. 1340.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-0573

Curr Probl Cancer. 2022 Mar 28. pii: S0147-0272(22)00019-8. [Epub ahead of print]46(3): 100859

Palbociclib and letrozole in hormone-receptor positive advanced breast cancer: Predictive response and prognostic factors.

Khalil El Gharib, Walid Macaron, Joseph Kattan, Mohamad Ali Salloum, Fadi Farhat, Marianne Smith, Fadi El Karak.

CDK 4/6 inhibitors have been yielding propitious results when with hormone therapy in the management of Her2-negative and hormone-receptor (HR)-positive metastatic breast cancer, palbociclib being one of the first molecules investigated in this setting. However, the response to CDK4/6 inhibitors is variable. To identify predictive and prognostic factors of response to this therapeutic regimen. Eligible patients were females with HR+ and Her2- advanced breast cancer, receiving Palbociclib in combination with Letrozole. PFS was the primary endpoint in the evaluation of response to treatment. This survival was then further segregated according to various characteristics: histological (type, grade, hormone receptors), metastatic site, line of treatment, response type at initial assessment, and best response achieved. The data was then processed by two statistical analysis models: Kaplan-Meier and univariate preceding multivariate Cox proportional risks. Sixty patients were included and followed for a median follow-up duration of 15.98 months. PFS recorded a median of 19.07 months (95% CI=15.43-22.71). PFS had a median of 12.99 months in the absence of progesterone receptors (vs 20.05 months in the case of positive estrogen and progesterone receptors; P = 0.046), a median of 13.02 months in the presence of liver metastases (vs 22.98 months in the absence of liver metastases; P = 0.007), and 15.94 months in the case of second-line and beyond (vs 22.98 months in the case of first-line; P = 0.033). Regarding the Hazard Ratio of progression, we note age (HR 0.941; P = 0.019), liver metastases (HR 2.751; P = 0.051), response at initial evaluation (HR<1; P < 0.001) and best response (HR<1; P = 0.003). PFS reached similar figures to those of international studies. The absence of progesterone receptors, presence of liver metastases, and use as second-line or beyond are associated with a reduced median PFS. One year age increase (protective factor), liver metastases (risk factor), response at initial evaluation, and best response achieved are identified as the most predictive factors of the response to this treatment regimen and of the progression risk.

DOI: https://doi.org/10.1016/j.currproblcancer.2022.100859

Sci Rep. 2022 Apr 05. 12(1): 5706

Novel therapeutic strategy for melanoma based on albendazole and the CDK4/6 inhibitor palbociclib.

Lin Zhu, Qin Yang, Rong Hu, Yanan Li, Yuanliang Peng, Hong Liu, Mao Ye, Bin Zhang, Peihe Zhang, Feng Liu-Smith, Hui Li, Jing Liu.

Although an increasing number of patients benefit from immunotherapy and targeted therapies, melanoma remains incurable with increasing incidence. Drug repositioning and repurposing is an alternative strategy to discover and develop novel anticancer drugs or combined therapeutic regimens. In this study, we demonstrated that albendazole (ABZ), an Food and Drug Administration (FDA)-approved broad-spectrum antiparasitic agent, significantly inhibits the proliferation of melanoma cells in vitro and in vivo. RNA sequencing and flow cytometry analysis revealed that ABZ arrests melanoma cells at the G2/M phase of the cell cycle and induces cell apoptosis. More importantly, the CDK4/6 inhibitor palbociclib, as a member of the first and only class of highly specific CDK inhibitors approved for cancer treatment to date, showed significant synergistic effects with ABZ treatment in melanoma cells and mouse models. Taken together, we revealed a previously unappreciated function of ABZ in antimelanoma proliferation by inducing cell cycle arrest and apoptosis and provided a novel combined therapeutic regimen of ABZ plus CDK4/6 inhibitor treatment in melanoma.

DOI: https://doi.org/10.1038/s41598-022-09592-0

Pharmacol Rep. 2022 Apr 03.

Palbociclib regulates intracellular lipids in mammary tumor cells by secreting lipoprotein lipase.

Tomoyasu Fujii, Jun Kamishikiryo, Tetsuo Morita.

BACKGROUND: Lipoprotein metabolism is essential for the growth and proliferation of cancer cells, and is involved in the supply of energy and cellular components. Lipoprotein lipase (LPL) is a very important enzyme in lipoprotein metabolism; however, the details underlying the mechanism of LPL secretion are unclear. Palbociclib is an antitumor drug that inhibits cell cycle progression and suppresses the growth of cancer cells. The effects of palbociclib on energy metabolism, particularly on lipid metabolism, have not been fully elucidated.
METHODS: We examined the regulation of LPL secretion, which is primarily involved in lipoprotein metabolism. FM3A mouse mammary tumor cells, which are hormone receptor-positive breast cancer cells, were treated with palbociclib, and the activity and protein levels of secreted LPL were measured. Moreover, the changes in intracellular lipid content were measured by fluorescence staining using Nile Red.
RESULTS: FM3A cells were treated with palbociclib, the activity and protein content of secreted LPL were increased. The stimulatory secretion of LPL by palbociclib was suppressed by an intracellular Ca2+ chelator (BAPTA-AM) and a Ca2+/calmodulin-dependent protein kinase kinase (CaMKK) inhibitor (STO-609). Furthermore, the palbociclib-stimulated secretion of LPL was not observed in AMP-activated protein kinase (AMPK)-knockdown cells. An increase in the fluorescence intensity of Nile Red was observed in palbociclib-treated cells; however, no increase was observed in LPL-knockdown cells.
CONCLUSIONS: Our data suggest that palbociclib causes intracellular lipid accumulation in breast cancer cells by stimulating Ca2+/CaMKK/AMPK-mediated LPL secretion.

Keywords: AMP-activated protein kinase; Breast cancer; Lipid accumulation; Lipoprotein lipase; Palbociclib

DOI: https://doi.org/10.1007/s43440-022-00365-0

Nanomedicine. 2022 Apr 04. pii: S1549-9634(22)00045-4. [Epub ahead of print] 102559

A nanomechanical strategy involving focal adhesion kinase for overcoming drug resistance in breast cancer.

Jinsol Choi, Soyeun Park.

Despite implementation of nanomechanical studies in cancer research, studies on the nanomechanical aspects of drug resistance in cancer are lacking. Here, we established the mechanical signatures of drug-resistant breast cancer cells using atomic force microscopy-based indentation techniques and functionalized nanopatterned substrates (NPS). Additionally, we examined the expression of proteins pertinent to focal adhesions in order to elucidate the molecular signatures responsible for the acquisition of drug resistance in breast cancer cells. Drug-resistant breast cancer cells exhibited mechanical reinforcement, increased actin stress fibers, dysfunctional mechano-reciprocal interaction with the NPS, vinculin overexpression, and improved focal adhesion kinase (FAK) activity. Owing to differences in FAK activation upon co-treatment with a FAK inhibitor, the drug-resistant breast cancer cells were eradicated more efficiently than invasive breast cancer cells having pro-survival activity. These findings demonstrated the potential of a novel co-treatment regimen using FAK inhibitors for overcoming drug resistance in breast cancer cells.

Keywords: Breast cancer; Chemotherapeutic resistance; Elastic moduli; Focal adhesion kinase; Mechano-reciprocity

DOI: https://doi.org/10.1016/j.nano.2022.102559