6) HER2 is a receptor tyrosine kinase that is overexpressed in a subset of breas

Question

6) HER2 is a receptor tyrosine kinase that is overexpressed in a subset of breast cancers. HER2+ breast cancers are typically treated with Trastuzumab, a HER2 antibody that inhibits HER2 activity. However, many patients eventually develop resistance to Trastuzumab, indicating that some tumor cells acquire mutations that bypasS HER2 signaling. Based on what you know about RTK signaling, propose a specific gene mutation that could allow a HER2+ cell to promote its own proliferation independently of HER2 and resist Trastuzumab. Explain. (3 points)

Explanation / Answer

Receptor Tyrosine Kinases (RTKs) are the transmembrane protein receptors that eventually help cells to interact with their neighbors in a tissue. RTKs differ from other cell surface receptors as they contain intrinsic enzyme activity. In particular, the binding of a signaling molecule with an RTK activates tyrosine kinase in the cytoplasmic tail of the receptor.

Receptor tyrosine kinases (RTKs) are the essential components of transduction of signal pathways that mediate cell-to-cell communication. These transmembrane receptors, which bind polypeptide ligands mainly -growth factors which play key roles in processes such as cellular growth, differentiation, metabolism and motility.

Trastuzumab, a humanized IgG1 monoclonal antibody against the extracellular domain of the HER2 receptor. The mechanisms of action of Trastuzumab is still unclear, but the proposed mechanisms include the inhibition of HER2 pathway which mediated angiogenesis and cell proliferation, immune response against tumor cells via antibody-dependent cell-mediated cytotoxicity (ADCC), acceleration of internalization and degradation of HER2 from the cell membrane leading to receptor downregulation, prevention of homodimerization of truncated HER2 receptors by inhibition of cleavage by metalloproteinases. It may also distrupt the HER2/Src interaction. It has sinergistic activity with various chemotherapy drugs, probably by inhibitng important survival pathway.

In the early-stage of breast cancer, adding trastuzumab to neo-adjuvant chemotherapy substantially improves the overall survival and reduces the risk of recurrence, both by 33%.Trastuzumab substantially improves outcomes in both early-stage and metastatic breast cancer, but not all patients respond to trastuzumab. This type of trastuzumab resistance is de novo HER2 resistance or intrinsic resistance. In the early-stages breast cancer, the addition of trastuzumab to neoadjuvant chemotherapy is associated with a complete response of the breast and lymph nodes in 38%–55% of patients, suggesting intrinsic resistance rate of 45%–62%. Some patients respond initially but progress some time after. In patients with metastatic breast cancer treated with trastuzumab and chemotherapy, the median duration of partial or CR is 9.1 months, suggesting that within 1-year patients acquire resistance.

Several proposed mechanisms are there for HER2 resistance, which include signaling through alternative pathways, upregulation of signaling pathways downstream of HER2, disrupted trastuzumab-HER2 receptor binding, and failure to elicit an appropriate immune response. Most important is the activation of PI3K/Akt/mTOR signaling which appears to play a keen role in both acquired and intrinsic HER2 resistance. Both preclinical and clinical data implicate PTEN loss and PI3CKA mutation in constitutive PI3K/Akt/mTOR signaling and de novo resistance to HER2-targeted therapy. For example, in one study of women with HER2-positive breast cancer treated with trastuzumab, patients who showed the loss of PTEN expression or PI3CKA mutation had a significantly shorter PFS. In another study, the loss of PTEN was associated with a significantly lower overall response rate. In vitro models of HER2-positive breast cancer have shown that the loss of PTEN expression and PI3CKA mutations are also markers of lapatinib resistance. Activation of the PI3K/Akt/mTOR pathway is also implicated in acquired resistance to HER2-targeted therapy.

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