bims-cyhorp 2022-01-23 papers

Issue of 2022–01–23
five papers selected by
Piotr Okupski,

Cancers (Basel). 2022 Jan 07. pii: 293. [Epub ahead of print]14(2):

The Renaissance of Cyclin Dependent Kinase Inhibitors.

Tobias Ettl, Daniela Schulz, Richard Josef Bauer.

Cyclin-dependent kinases (CDK) regulate cell cycle progression. During tumor development, altered expression and availability of CDKs strongly contribute to impaired cell proliferation, a hallmark of cancer. In recent years, targeted inhibition of CDKs has shown considerable therapeutic benefit in a variety of tumor entities. Their success is reflected in clinical approvals of specific CDK4/6 inhibitors for breast cancer. This review provides a detailed insight into the molecular mechanisms of CDKs as well as a general overview of CDK inhibition. It also summarizes the latest research approaches and current advances in the treatment of head and neck cancer with CDK inhibitors. Instead of monotherapies, combination therapies with CDK inhibitors may especially provide promising results in tumor therapy. Indeed, recent studies have shown a synergistic effect of CDK inhibition together with chemo- and radio- and immunotherapy in cancer treatment to overcome tumor evasion, which may lead to a renaissance of CDK inhibitors.

Keywords: CDK; CDK4/CDK6; CDKI; HNSCC; PD-L1; abemaciclib; cell cycle inhibition/blockade; chemosensitization; flavopiridol; immunosensitization; palbociclib; radiosensitization; ribociclib; seliciclib; synergy; trilaciclib

DOI: https://doi.org/10.3390/cancers14020293

EMBO J. 2022 Jan 17. e108599

CDK4/6 inhibitors induce replication stress to cause long-term cell cycle withdrawal.

Lisa Crozier, Reece Foy, Brandon L Mouery, Robert H Whitaker, Andrea Corno, Christos Spanos, Tony Ly, Jeanette Gowen Cook, Adrian T Saurin.

CDK4/6 inhibitors arrest the cell cycle in G1-phase. They are approved to treat breast cancer and are also undergoing clinical trials against a range of other tumour types. To facilitate these efforts, it is important to understand why a cytostatic arrest in G1 causes long-lasting effects on tumour growth. Here, we demonstrate that a prolonged G1 arrest following CDK4/6 inhibition downregulates replisome components and impairs origin licencing. Upon release from that arrest, many cells fail to complete DNA replication and exit the cell cycle in a p53-dependent manner. If cells fail to withdraw from the cell cycle following DNA replication problems, they enter mitosis and missegregate chromosomes causing excessive DNA damage, which further limits their proliferative potential. These effects are observed in a range of tumour types, including breast cancer, implying that genotoxic stress is a common outcome of CDK4/6 inhibition. This unanticipated ability of CDK4/6 inhibitors to induce DNA damage now provides a rationale to better predict responsive tumour types and effective combination therapies, as demonstrated by the fact that CDK4/6 inhibition induces sensitivity to chemotherapeutics that also cause replication stress.

Keywords: CDK6; Palbociclib; cyclin-dependent kinase; replication stress; senescence

DOI: https://doi.org/10.15252/embj.2021108599

Curr Probl Cancer. 2022 Jan 10. pii: S0147-0272(21)00167-7. [Epub ahead of print] 100832

Thrombotic events in patients using cyclin dependent kinase 4/6 inhibitors, analysis of existing ambulatory risk assessment models and the potential influences of tumor specific risk factors.

Malinda T West, Thomas Kartika, Ashley R Paquin, Erik Liederbauer, Tony J Zheng, Lucy Lane, Kyaw Thein, Joseph J Shatzel.

Cyclin dependent kinase 4 of 6 inhibitors (CDKi) are key therapeutics in the treatment of advanced breast cancer and have recently been approved in small cell lung cancer for the prevention of myelosuppression. Thrombotic events have emerged as a significant treatment related adverse event in up to 5% of patients in clinical trials and has been reported at higher rates, up to 10%, in real world analysis. The prothrombotic mechanisms of CDKis, however, remain unknown. Cancer specific risk assessment models exist to identify who may be at highest risk of thrombosis and who could potentially benefit from prophylactic anticoagulation. However, these models may not be accurate in patients taking CDKis and may not fully capture recently identified thrombotic risk factors such as tumor specific somatic mutations. In the following manuscript, we summarize the literature on thrombotic events with CDKis in clinical trials and real-world settings, review the existing thrombosis risk assessment models for ambulatory cancer patients, and discuss the literature on tumor mutations and role in cancer associated thrombosis.

DOI: https://doi.org/10.1016/j.currproblcancer.2021.100832

Clin Breast Cancer. 2021 Dec 20. pii: S1526-8209(21)00369-4. [Epub ahead of print]

Quality-Adjusted Survival with Ribociclib Plus Fulvestrant Versus Placebo Plus Fulvestrant in Postmenopausal Women with HR±HER2- Advanced Breast Cancer in the MONALEESA-3 Trial.

Guy Jerusalem, Thomas E Delea, Migule Martin, Michelino De Laurentiis, Arnd Nusch, J Thaddeus Beck, Arlene Chan, Seock-Ah Im, Patrick Neven, Alexander Lonshteyn, David Chandiwana, Brad Lanoue, Peter A Fasching.

BACKGROUND: MONALEESA-3 demonstrated an overall survival (OS) benefit for ribociclib plus fulvestrant (R+F) in postmenopausal women with hormone receptor (HR) positive, HER2 negative advanced breast cancer (ABC). This study estimated quality-adjusted (QA) survival outcomes for patients receiving R+F vs. placebo (P)+F in MONALEESA-3.
METHODS: Kaplan-Meier OS was partitioned into health states: (1) toxicity (TOX)=time spent with grade 3 -4 adverse events before progression (DP); (2) progression (PROG)=time between DP and death; and (3) time without symptoms or toxicity (TWiST)=time not in TOX or PROG. QA time was calculated by combining estimated mean time in each health state with treatment-group specific health-state utility values estimated using EQ-5D-5L questionnaire. Outcomes included QA progression-free survival (QAPFS), QAOS, and QA TWiST (Q-TWiST). Q-TWiST was calculated with health-state utility values for TOX and PROG defined relative to TWiST.
RESULTS: Mean PFS and OS were significantly greater with R+F vs. P+F (difference 0.56 and 0.19 years). Mean time in TOX and TWiST were greater with R+F; mean time in PROG was greater with P+F. QAPFS was 0.45 years (95% CI 0.27 -0.63) greater with R+F than P+F (P <.001). QAOS was numerically greater with R+F vs. P+F (0.16 years, 95% CI 0.07 -0.45, P = .0569). Q-TWiST was 0.23 years greater with R+F (95% CI 0.07 -0.45, P = .0069). In a sensitivity analysis using an estimate of disutility for PROG, the difference in QAOS was 0.23 years (95% CI 0.08 -0.41, P = .0022).
CONCLUSION: R+F in postmenopausal women with HR+/HER2- ABC improves QAPFS, resulting in clinically important improvements in Q-TWiST and may improve QAOS.

Keywords: Breast cancer; Fulvestrant; Postmenopausal; Quality of life; Ribociclib; Survival

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

Oncotarget. 2022 ;13 92-104

GZ17-6.02 and palbociclib interact to kill ER+ breast cancer cells.

Laurence Booth, Cameron West, Robert P Moore, Daniel Von Hoff, Paul Dent.

GZ17-6.02 is presently undergoing clinical evaluation in solid tumors and lymphoma. The present studies were performed to define its biology in estrogen receptor positive breast cancer cells and to determine whether it interacted with palbociclib to enhance tumor cell killing. GZ17-6.02 interacted in an additive fashion with palbociclib to kill ER+ breast cancer cells. GZ17-6.02 and palbociclib cooperated to inactivate mTOR and AKT and to activate ULK1 and PERK. The drugs interacted to increase the expression of FAS-L and BAX, and to decrease the levels of MCL1, the estrogen receptor, and HDACs 1-3. Palbociclib activated ERBB3, an effect blocked by GZ17-6.02. GZ17-6.02 and palbociclib interacted to increase the expression of multiple toxic BH3 domain proteins and to reduce MCL1 and BCL-XL expression. Knock down of FAS-L reduced the lethality of [GZ17-6.02 + palbociclib]. GZ17-6.02 and palbociclib interacted to enhance autophagosome formation and autophagic flux. Knock down of Beclin1, ATG5, BAG3, eIF2α, toxic BH3 domain proteins or CD95 significantly reduced drug combination lethality. GZ17-6.02 and palbociclib increased the expression of Beclin1 and ATG5, effects blocked by knock down of eIF2α. The drugs also increased the phosphorylation of the AMPK and ATG13, effects blocked by knock down of ATM. Knock down of ATM or the AMPK, or expression of activated mTOR significantly reduced the abilities of GZ17-6.02 and palbociclib to enhance autophagosome formation and autophagic flux.

Keywords: 5FU; GZ17-6.02; autophagy; breast cancer; palbociclib

DOI: https://doi.org/10.18632/oncotarget.28177