bims-cyhorp 2022-04-03 papers

bims-cyhorp

Biomed News

on Cyclin-dependent kinases in hormone receptor positive breast cancer

Issue of 2022‒04‒03
eight papers selected by
Piotr Okupski

The Resistance of Cancer Cells to Palbociclib, a Cyclin-Dependent Kinase 4/6 Inhibitor, is Mediated by the ABCB1 Transporter.
Treatment Strategy for Patients with HR-Positive HER2-Negative Metastatic Breast Cancer That Progressed on CDK4/6 Inhibitors.
Safety in Japanese Advanced Breast Cancer Patients Who Received Abemaciclib in MONARCH 2 and MONARCH 3: Assessment of Treatment-Emergent Neutropenia, Diarrhea, and Increased Alanine Aminotransferase and Aspartate Aminotransferase Levels.
Early Switch to Fulvestrant Plus Palbociclib Improves Outcomes in ESR1-Mutated, Estrogen Receptor-Positive Metastatic Breast Cancer.
Evaluating the Response of Palbociclib on Progression Free Survival in Hormone Receptor Positive Metastatic Breast Cancer.
Ribociclib-induced extensive vitiligo-like lesions: possible pathomechanisms with clinical, dermoscopic and histological correlation.
Reciprocal regulation of p21 and Chk1 controls the Cyclin D1-RB pathway to mediate senescence onset after G2 arrest.
Palbociclib in combination with sunitinib exerts a synergistic anti-cancer effect in patient-derived xenograft models of various human cancers types.

Front Pharmacol. 2022 ;13 861642

The Resistance of Cancer Cells to Palbociclib, a Cyclin-Dependent Kinase 4/6 Inhibitor, is Mediated by the ABCB1 Transporter.

Han Fu, Zhuo-Xun Wu, Zi-Ning Lei, Qiu-Xu Teng, Yuqi Yang, Charles R Ashby, Yixiong Lei, Yuyin Lian, Zhe-Sheng Chen.

  Palbociclib was approved by the United States Food and Drug Administration for use, in combination with letrozole, as a first-line treatment for estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) postmenopausal metastatic breast cancer. However, recent studies show that palbociclib may be an inhibitor of the ABCB1 transporter, although this remains to be elucidated. Therefore, we conducted experiments to determine the interaction of palbociclib with the ABCB1 transporter. Our in vitro results indicated that the efficacy of palbociclib was significantly decreased in the ABCB1-overexpressing cell lines. Furthermore, the resistance of ABCB1-overexpressing cells to palbociclib was reversed by 3 μM of the ABCB1 inhibitor, verapamil. Moreover, the incubation of ABCB1-overexpressing KB-C2 and SW620/Ad300 cells with up to 5 μM of palbociclib for 72 h, significantly upregulated the protein expression of ABCB1. The incubation with 3 µM of palbociclib for 2h significantly increased the intracellular accumulation of [3H]-paclitaxel, a substrate of ABCB1, in ABCB1 overexpressing KB-C2 cells but not in the corresponding non-resistant parental KB-3-1 cell line. However, the incubation of KB-C2 cells with 3 μM of palbociclib for 72 h decreased the intracellular accumulation of [3H]-paclitaxel due to an increase in the expression of the ABCB1 protein. Palbociclib produced a concentration-dependent increase in the basal ATPase activity of the ABCB1 transporter (EC50 = 4.73 μM). Molecular docking data indicated that palbociclib had a high binding affinity for the ABCB1 transporter at the substrate binding site, suggesting that palbociclib may compete with other ABCB1 substrates for the substrate binding site of the ABCB1. Overall, our results indicate that palbociclib is a substrate for the ABCB1 transporter and that its in vitro anticancer efficacy is significantly decreased in cancer cells overexpressing the ABCB1.

Keywords:  ABCB1; ATP-binding cassette transporter; CDK4/6 inhibitor; multidrug resistance; palbociclib

DOI:  https://doi.org/10.3389/fphar.2022.861642
Breast Care (Basel). 2022 Feb;17(1): 16-23

Treatment Strategy for Patients with HR-Positive HER2-Negative Metastatic Breast Cancer That Progressed on CDK4/6 Inhibitors.

Shouko Hayama, Rikiya Nakamura, Toshiko Miyaki, Makiko Itami, Naohito Yamamoto.

  Background/Aims: The study aim was to evaluate if mTOR inhibitors can be considered as a treatment option for HR+ HER2- metastatic breast cancer (MBC) after progression on CDK4/6 inhibitors in clinical practice.Methods: We retrospectively collected the clinicopathological data of patients with HR+ HER2- MBC treated with CDK4/6 inhibitors and subsequent therapies at our institution between 2014 and 2020. The patients were divided into 3 groups according to the type of subsequent treatment: (A) exemestane plus everolimus, (B) endocrine monotherapy, and (C) chemotherapy. Overall survival (OS) was estimated by using the Kaplan-Meier method and compared by using the log-rank test. The efficacy and adverse events (AEs) of each subsequent treatment were assessed by using Fisher's exact tests.
Results: Eighty-six patients (34 in group A, 20 in group B, 32 in group C) were included. The most common endocrine therapy in group B was fulvestrant (40%). The major chemotherapy regimen in group C was eribulin (25%). The median OS times after stopping CDK4/6 inhibitors were 34.5 months (95% confidence interval, 17.2 to NA), 13.6 months (3.9 to NA), and 19.5 months (18.8 to NA) in group A, group B, and group C, respectively. The only significant difference in OS was observed between group A and group B (20.9 months; p = 0.003). There was no difference in the incidence of grade 3 AEs between groups A and C or in the frequency of treatment discontinuation because of AEs among the 3 groups.
Conclusion: Our study shows that mTOR inhibitors might be an effective treatment option for patients with HR+ HER2- MBC previously treated with CDK4/6 inhibitors.

Keywords:  CDK4/6 inhibitors; Endocrine therapy; Metastatic breast cancer; mTOR inhibitors

DOI:  https://doi.org/10.1159/000515729
Cancer Manag Res. 2022 ;14 1179-1194

Safety in Japanese Advanced Breast Cancer Patients Who Received Abemaciclib in MONARCH 2 and MONARCH 3: Assessment of Treatment-Emergent Neutropenia, Diarrhea, and Increased Alanine Aminotransferase and Aspartate Aminotransferase Levels.

Norikazu Masuda, Yucherng Chen, Tsutomu Kawaguchi, Koji Dozono, Masakazu Toi.

  Purpose: Our objective was to gain a better understanding of the safety of abemaciclib in Japanese patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer.Patients and Methods: Treatment-emergent adverse events (TEAEs) were assessed in pooled Japanese subpopulation data from two phase 3 studies assessing abemaciclib/placebo in combination with fulvestrant (MONARCH 2; M2) or non-steroidal aromatase inhibitors (MONARCH 3; M3). For common, clinically relevant TEAEs, event characteristics and management were summarized by study.
Results: In the Japanese safety subpopulation (abemaciclib: N=101; placebo: N=46), all patients experienced ≥1 TEAE (Grade ≥ 3: abemaciclib, 71.3%; placebo, 23.9%; no Grade 5). Clinically relevant TEAEs that were more frequent in abemaciclib-treated Japanese patients compared to the overall safety populations included diarrhea (any grade, 95.0%; Grade ≥ 3, 12.9%), neutropenia (any grade, 75.2%; Grade 3-4, 35.6%), increased alanine aminotransferase (ALT; any grade, 39.6%; Grade 3-4, 14.9%), and increased aspartate aminotransferase (AST; any grade, 37.6%; Grade 3-4, 8.9%). Diarrhea was Grade ≤3 and successfully managed with medications (≥87%) and dose reductions (≤25%) and/or omissions (≤23.3%). Most Grade ≥2 diarrhea occurred in the first treatment cycle, declining thereafter. Neutropenia, the most common Grade ≥3 TEAE in abemaciclib-treated Japanese patients, was generally manageable with dose omissions (M2: 42.0%; M3: 23.1%) and/or reductions (M2: 16%; M3: 15.4%). Neutrophil counts plateaued after Cycle 2, recovering to pretreatment levels after discontinuation of abemaciclib. Hepatic events were managed with medication (≤21%) and dose adjustments (≤33.3%), with most Grade ≥2 events occurring in early treatment cycles. Discontinuation of any study treatment in Japanese patients occurred more frequently due to increased ALT/AST (M2: 9.1%/10.5%; M3: 16.7%/10.5%) compared with diarrhea (M2: 0%; M3: 2.8%) or neutropenia (M2: 0%; M3: 3.8%).
Conclusion: Abemaciclib was well tolerated in Japanese patients in MONARCH 2 and MONARCH 3, with common, clinically relevant TEAEs manageable with appropriate interventions.

Keywords:  abemaciclib; breast cancer; cyclin-dependent kinase 4/6; fulvestrant; nonsteroidal aromatase inhibitor

DOI:  https://doi.org/10.2147/CMAR.S348591
Oncologist. 2022 Mar 28. 27(Supplement_1): S9-S10

Early Switch to Fulvestrant Plus Palbociclib Improves Outcomes in ESR1-Mutated, Estrogen Receptor-Positive Metastatic Breast Cancer.

Anne Jacobson.

DOI: https://doi.org/10.1093/oncolo/oyac016
Oncology. 2022 Mar 28.

Evaluating the Response of Palbociclib on Progression Free Survival in Hormone Receptor Positive Metastatic Breast Cancer.

Sufana Shikdar, Spencer Hall, Brandon Taylor, Jennifer de Los Angeles, Mashal Tahirkheli, Daniel Zhao, Wajeeha Razaq.

BACKGROUND: In patients with hormone receptor positive metastatic breast cancer, Palbociclib has been shown to improve overall survival and progression-free survival (PFS) when combined with endocrine therapy. Dose modification of palbociclib is effective in the management of adverse events. Despite variable clinical response, no predictive biomarkers of efficacy to palbociclib have been identified in metastatic breast cancer. In our study, we aimed to assess the PFS of metastatic breast cancer patients who received dose-reduced palbociclib and compare the results in the non-dose reduced group. We also evaluated the clinical significance of progesterone receptor (PR) and Ki67 as predictive biomarkers of palbociclib.METHODS: Seventy-six palbociclib-treated metastatic breast cancer patients were included in our study. PFS was compared between dose reduced and non-dose reduced groups. PR expression and Ki67 status were assessed by immunohistochemistry (IHC). Kaplan-Meier method and log-rank test were used to analyze PFS.
RESULTS: Of the 76 patients, 40 (52.6%) experienced dose reduction. Statistical analysis of the results revealed that there were no statistically significant differences observed between dose-reduced (16.5 months) vs non-dose reduced (17.7 months) patients in PFS (p=0.5493). For patients with Ki67 ≥ 14%, PFS was 15.2 months (95% CI: 10.2 to 22.2 months; p= 0.3024). In patients with PR ≥ 20%, median PFS was 25.0 months (lower 95% CI: 16.8 months; p=0.0069).
CONCLUSION: Our study indicated that dose reduction of palbociclib is frequently required but does not appear to affect PFS. PR expression was suggested to be a significant predictive factor for palbociclib responsiveness.

DOI: https://doi.org/10.1159/000524340
BMJ Case Rep. 2022 Apr 01. pii: e248782. [Epub ahead of print]15(4):

Ribociclib-induced extensive vitiligo-like lesions: possible pathomechanisms with clinical, dermoscopic and histological correlation.

Gopikrishnan Anjaneyan, Pavithran Keechilat, Prasanna Duraisamy, Malini Eapen.

  Cyclin dependent kinase (CDK) 4/6 inhibitors are targeted agents which act on cyclin-D and these combined with hormonal therapy have been approved for the treatment of locally advanced or metastatic breast cancer. CDK 4/6 inhibitors have been found to have a tolerable adverse event profile; however, they have been associated with various dermatological adverse events. We report a case of ribociclib-induced vitiligo and discuss the clinical, dermoscopic and histological features with a review of the various possible pathomechanisms involved.

Keywords:  Breast cancer; Chemotherapy; Dermatology; Drugs and medicines; Oncology

DOI:  https://doi.org/10.1136/bcr-2022-248782
J Cell Sci. 2022 Mar 28. pii: jcs.259114. [Epub ahead of print]

Reciprocal regulation of p21 and Chk1 controls the Cyclin D1-RB pathway to mediate senescence onset after G2 arrest.

Gerald Lossaint, Anđela Horvat, Véronique Gire, Katarina Bacevic, Karim Mrouj, Fabienne Charrier-Savournin, Virginie Georget, Daniel Fisher, Vjekoslav Dulic.

  Senescence is an irreversible proliferation withdrawal that can be initiated after DNA damage-induced cell cycle arrest in G2 phase to prevent genomic instability. Senescence onset in G2 requires p53 and RB family tumour suppressors, but how they are regulated to convert a temporary cell cycle arrest into a permanent one remains unknown. Here, we show that a previously unrecognised balance between the CDK inhibitor p21 and Chk1 controls D-type cyclin-CDK activity during G2 arrest. In non-transformed cells, p21 activates RB in G2 by inhibiting Cyclin D1-CDK2/CDK4. The resulting G2 exit, which precedes appearance of senescence markers, is associated with a mitotic bypass, Chk1 downregulation and DNA damage foci reduction. In p53/RB-proficient cancer cells, compromised G2 exit correlates with sustained Chk1 activity, delayed p21 induction, untimely Cyclin E1 re-expression and genome reduplication. Conversely, Chk1 depletion promotes senescence by inducing p21 binding to Cyclin D1 and Cyclin E1-CDK complexes and down-regulating CDK6, whereas Chk2 knockdown enables RB phosphorylation and delays G2 exit. In conclusion, p21 and Chk2 oppose Chk1 to maintain RB activity, thus promoting DNA damage-induced senescence onset in G2.

Keywords:  CDK6; Chk1; DNA damage checkpoints; G2 arrest after DNA damage; Senescence; p21

DOI:  https://doi.org/10.1242/jcs.259114
Cancer Lett. 2022 Mar 28. pii: S0304-3835(22)00148-3. [Epub ahead of print] 215665

Palbociclib in combination with sunitinib exerts a synergistic anti-cancer effect in patient-derived xenograft models of various human cancers types.

Neta Moskovits, Idit Peretz, Eva Chausky, Ella Itzhaki, Nofar Shmuel, Raisa Meerson, Nataly Tarasenko, Aleksandr Kaufman, Amos Stemmer, Ranny Yaﬀe, Avital Bareket-Samish, Natalia Edison, Tal Goldman, Salomon M Stemmer.

  The efficacy/safety of combining palbociclib (a CDK4/6 inhibitor) and sunitinib (a multi-targeted receptor tyrosine kinase inhibitor) was evaluated, using patient-derived xenograft (PDX) models. Twenty-three PDX mice models were developed from patients with various solid tumors. The mice were randomized to 4 groups (5-6 mice in each): control/palbociclib (100 mg/kg)/sunitinib (50 mg/kg)/combination. Drugs were administered orally, 5 days/week. In 17/23 PDX models (74%), the combination demonstrated a synergistic inhibitory effect vs the monotherapies ("responder" models) with no unexpected toxicities. In 13/17 responder models, where standard-of-care (SOC) was an additional comparator, the combination was more effective than SOC in 7 models, as effective in 4, and less effective in 2. The mean ± SEM experiment duration in 15/17 responder models (2/17 were excluded due to technical issues) was 86 ± 12 and 31 ± 5 days for the combination and control groups, respectively (p = 0.0002). The effect of the combination was dose-dependent. Cell-viability experiments in A549/MDA-MB-231/HT-29 cell lines and experiments using tumor-derived primary cell spheroids supported the PDX findings. In conclusion, combination of palbociclib and sunitinib exerts a synergistic anti-tumor effect without adding unexpected toxicity. A clinical trial assessing this combination is underway.

Keywords:  Efficacy; PDX models; Palbociclib; Sunitinib; Synergy

DOI:  https://doi.org/10.1016/j.canlet.2022.215665