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Related Concept Videos

Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
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Combination Therapies and Personalized Medicine

Combining two or more treatment methods increases the life span of cancer patients while reducing damage to vital organs or tissue from the overuse of a single treatment. Combination therapy also targets different cancer-inducing pathways, thus reducing the chances of developing resistance to treatment.
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Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
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Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
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M-Cdk Drives Transition Into Mitosis

Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or halt it in problematic ones. This regulation is known as the cell cycle control system.
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M cyclin...
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Treatment Resistent Cancers

Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...

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Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
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Precision Endocrine-Based Combinations After CDK4/6 Inhibitor Progression in HR-Positive Metastatic Breast Cancer.

Hikmat Abdel-Razeq1,2

  • 1Section of Hematology and Medical Oncology, Department of Internal Medicine, King Hussein Cancer Center, Amman, 11941, Jordan.

Drug Design, Development and Therapy
|July 14, 2026
PubMed
Summary

New targeted therapies and biomarker testing offer improved treatment options for hormone receptor-positive breast cancer patients who develop resistance to endocrine therapy (ET) and CDK4/6 inhibitors.

Keywords:
CDK4/6 inhibitorsESR1PI3K/AKT/mTORctDNAendocrine therapymetastatic breast cancerprecision therapy

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Area of Science:

  • Oncology
  • Endocrinology
  • Genetics

Background:

  • CDK4/6 inhibitors plus endocrine therapy (ET) improve outcomes in HR+/HER2- breast cancer but acquired resistance is common.
  • Resistance mechanisms include ESR1 mutations, PI3K/AKT/mTOR pathway activation, and cell-cycle deregulation.
  • Traditional treatment progression involved chemotherapy, but molecular advances enable targeted strategies.

Purpose of the Study:

  • To review the mechanisms of endocrine resistance in HR+/HER2- breast cancer.
  • To evaluate emerging targeted therapies for endocrine-resistant disease.
  • To outline a framework for biomarker-driven treatment sequencing after progression on prior therapy.

Main Methods:

  • Review of current literature on endocrine resistance mechanisms and targeted therapies.
  • Analysis of clinical trial data for novel agents like oral SERDs (elacestrant, imlunestrant) and PI3K/AKT inhibitors (alpelisib, capivasertib).
  • Discussion of the role of circulating tumor DNA (ctDNA) for resistance mutation detection and treatment guidance.

Main Results:

  • Oral selective estrogen receptor degraders (SERDs) show efficacy in ESR1-mutant tumors.
  • PI3K and AKT pathway inhibitors can overcome resistance when combined with endocrine therapy.
  • Molecularly guided therapy switching using ctDNA testing demonstrates potential to delay progression.

Conclusions:

  • Targeted endocrine-based combinations are preferred after progression, delaying chemotherapy.
  • Biomarker-driven sequencing optimizes treatment selection for advanced HR+/HER2- breast cancer.
  • Advances in understanding resistance biology and drug development are shifting the treatment paradigm.