Selective CDK4/6 Inhibitors: Biologic Outcomes, Determinants of Sensitivity, Mechanisms of Resistance, Combinatorial Approaches, and Pharmacodynamic Biomarkers

Knudsen, Erik S.; Shapiro, Geoffrey I.; Keyomarsi, Khandan

doi:10.1200/edbk_281085

Cited by 17 publications

(19 citation statements)

References 83 publications

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“…Although there has been considerable progress in the development of better and more targeted drugs for breast cancer treatment, the acquisition of resistance to drug treatments is common and limits their long-term use in patients with all subtypes of breast cancer [ 13 , 14 , 15 , 16 , 29 , 30 , 31 , 32 , 33 , 34 ]. Our findings in inhibitor sensitive and resistant cells provide new understanding of transcriptional and proteomic perturbations that accompany the acquisition of resistance, and they highlight changes that might provide new therapeutic modalities to target.…”

Section: Discussionmentioning

confidence: 99%

Transcription Regulation and Genome Rewiring Governing Sensitivity and Resistance to FOXM1 Inhibition in Breast Cancer

Ziegler

Guillen

Kim

et al. 2021

Cancers

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Forkhead box M1 (FOXM1), an oncogenic transcription factor associated with aggressiveness and highly expressed in many cancers, is an emerging therapeutic target. Using novel 1,1-diarylethylene-diammonium small molecule FOXM1 inhibitors, we undertook transcriptomic, protein, and functional analyses to identify mechanisms by which these compounds impact breast cancer growth and survival, and the changes that occur in estrogen receptor (ERα)-positive and triple negative breast cancer cells that acquire resistance upon long-term treatment with the inhibitors. In sensitive cells, these compounds regulated FOXM1 gene networks controlling cell cycle progression, DNA damage repair, and apoptosis. Resistant cells showed transcriptional alterations that reversed the expression of many genes in the FOXM1 network and rewiring that enhanced inflammatory signaling and upregulated HER2 or EGFR growth factor pathways. ERα-positive breast cancer cells that developed resistance showed greatly reduced ERα levels and responsiveness to fulvestrant and a 10-fold increased sensitivity to lapatinib, suggesting that targeting rewired processes in the resistant state may provide benefits and prolong anticancer effectiveness. Improved understanding of how FOXM1 inhibitors suppress breast cancer and how cancer cells can defeat their effectiveness and acquire resistance should be helpful in directing further studies to move these agents towards translation into the clinic.

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Section: Discussionmentioning

confidence: 99%

Transcription Regulation and Genome Rewiring Governing Sensitivity and Resistance to FOXM1 Inhibition in Breast Cancer

Ziegler

Guillen

Kim

et al. 2021

Cancers

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“…Several retrospective clinical analyses 18,23,30,37 and preclinical studies 32,33,38,39 report that either cyclin-E1 gene amplification or elevated gene expression has significant treatment interaction effects for CDK4/6 inhibition, supporting cyclin-E1 as a potential intrinsic resistance biomarker (Fig 3). 40,41 In PALOMA-3 (n = 302), palbociclib efficacy was lower in patients with high cyclin-E1 gene expression levels. Tumor profiling was performed using the EdgeSeq Oncology BM Panel for 2,534 cancer-related genes (HTG Molecular Diagnostics, Tucson, AZ) in baseline biopsies before treatment.…”

Section: Molecular Biomarkers For Treatment Resistancementioning

confidence: 99%

Systematic Review of Molecular Biomarkers Predictive of Resistance to CDK4/6 Inhibition in Metastatic Breast Cancer

Asghar

Kanani

Roylance

et al. 2022

JCO Precision Oncology

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Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have revolutionized the treatment of hormone-positive metastatic breast cancers (mBCs). They are currently established as standard therapies in combination with endocrine therapy as first- and second-line systemic treatment options for both endocrine-sensitive and endocrine-resistant mBC populations. In the first-line metastatic setting, the median progression-free survival for the three currently approved CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, with aromatase inhibitors is greater than 2 years (palbociclib 27.6 months; ribociclib 25.3 months; and abemaciclib 28.18 months). Although CDK4/6 inhibitors have significant clinical benefits and enable physicians to delay starting chemotherapy, they are expensive and can be associated with drug toxicities. Here, we have performed a systemic review of the reported molecular markers predictive of drug response including intrinsic and acquired resistance for CDK4/6 inhibition in mBC. The rapidly emerging molecular landscape is captured through next-generation sequencing of breast cancers (DNA with or without RNA), liquid biopsies (circulating tumor DNA), and protein analyses. Individual molecular candidates with robust and reliable evidence are discussed in more depth.

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“…To date, no one specific genetic aberration is indicative of sensitivity to CDK inhibitors, whereas activation of CDK4/6 is too complex to allow the use of these proteins as predictive biomarkers 26 . Various potential candidate biomarkers have, however, been identified, including phospho‐retinoblastoma (pRB), RB1 mutations, cyclin D1 (CCND1) amplifications, and cyclin E1 (CCNE1) overexpression, 27,28 but their clinical utility remains unproven.…”

Section: Which Patients Should Receive Adjuvant Abemaciclib?mentioning

confidence: 99%

Adjuvant cyclin‐dependent kinase 4/6 inhibition in hormone receptor–positive breast cancer: One Monarch to rule them all?

Dhakal

Falkson

O’Regan

2021

Cancer

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The use of cyclin‐dependent kinase 4/6 (CDK4/6) inhibitors has dramatically improved outcomes for patients with metastatic, hormone receptor (HR)–positive breast cancer. Because of the continued high rate of relapse in patients with node‐positive, HR‐positive disease, evaluating these agents in the adjuvant setting is the logical next step. Three adjuvant CDK inhibitor trials have been reported to date, with only 1 of them showing a statistical advantage for the CDK inhibitor in comparison with endocrine therapy alone. These trials have key similarities and differences that could explain the disparate results. The one positive trial has a relatively short follow‐up, and continued analysis is critical to confirm the benefit of adjuvant CDK inhibition in this setting. It is imperative that predictive biomarkers be determined so that these agents can be used in the patients most likely to benefit and thus the additional toxicity and expense can be avoided in those who do not require these agents. Lay Summary There is a critical need for new agents to prevent relapse in patients with hormone receptor–positive breast cancer. Trials to date evaluating cyclin‐dependent kinase inhibitors, which decrease how quickly cancer cells multiply, have shown mixed results, with only 1 trial demonstrating that these agents decrease recurrence.

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Selective CDK4/6 Inhibitors: Biologic Outcomes, Determinants of Sensitivity, Mechanisms of Resistance, Combinatorial Approaches, and Pharmacodynamic Biomarkers

Cited by 17 publications

References 83 publications

Transcription Regulation and Genome Rewiring Governing Sensitivity and Resistance to FOXM1 Inhibition in Breast Cancer

Transcription Regulation and Genome Rewiring Governing Sensitivity and Resistance to FOXM1 Inhibition in Breast Cancer

Systematic Review of Molecular Biomarkers Predictive of Resistance to CDK4/6 Inhibition in Metastatic Breast Cancer

Adjuvant cyclin‐dependent kinase 4/6 inhibition in hormone receptor–positive breast cancer: One Monarch to rule them all?

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