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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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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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Related Experiment Video

Updated: Aug 23, 2025

Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down
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Resistance to Trastuzumab.

Sneha Vivekanandhan1, Keith L Knutson1

  • 1Department of Immunology, Mayo Clinic, 4500 San Pablo Rd., Jacksonville, FL 32224, USA.

Cancers
|October 27, 2022
PubMed
Summary

Trastuzumab is a key breast cancer biologic targeting HER2. This review explores new resistance mechanisms like immune suppression and metabolic escape, aiming for improved patient survival through tailored therapies.

Keywords:
antibody drug conjugateherceptinimmune responsesmonoclonal antibodypertuzumabtyrosine kinase inhibitorvaccine

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Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Trastuzumab is a critical biologic therapy for HER2-positive breast cancer.
  • Its efficacy relies on multiple mechanisms, including ADCC and apoptosis induction.
  • However, primary and adaptive resistance limit its clinical success.

Purpose of the Study:

  • To review novel molecular and cellular mechanisms of trastuzumab resistance.
  • To discuss how these resistance pathways can inform combination therapy strategies.
  • To highlight potential avenues for improving patient survival in HER2-positive breast cancer.

Main Methods:

  • Literature review of recent studies on trastuzumab resistance.
  • Analysis of molecular and cellular pathways contributing to treatment failure.
  • Synthesis of findings to propose future therapeutic approaches.

Main Results:

  • Identified key resistance mechanisms: immune suppression, vascular mimicry, cancer stem cells, lncRNA deregulation, and metabolic escape.
  • Highlighted the role of the adaptive immune system in trastuzumab action and resistance.
  • Emphasized the heterogeneity of resistance pathways in breast cancer patients.

Conclusions:

  • Understanding novel resistance mechanisms is crucial for overcoming therapeutic limitations.
  • Developing patient-tailored combination therapies targeting these pathways can enhance treatment efficacy.
  • Further research into these mechanisms promises to improve outcomes for breast cancer patients.