Neu Perspectives, Therapies, and Challenges for Metastatic HER2-Positive Breast Cancer

Abstract

Even though gene amplification or protein overexpression occurs in approximately one-fifth of all breast cancers, the discovery of HER2 has, nevertheless, had profound implications for the disease. Indeed, the characterization of the receptor resulted in a number of significant advances. Structurally, unique features provided avenues for the development of numerous compounds with target-specificity; molecularly, biological constructs revealed a highly complex, internal signal transduction pathway with regulatory effects on tumor proliferation, survival, and perhaps, even resistance; and clinically, disease outcomes manifested its predictive and prognostic value. Yet despite the receptor's utility, the beneficial effects are diminished by tumor recurrence after neo-or adjuvant therapy as well as losses resulting from the inability to cure patients with metastatic disease. What these observations suggest is that while tumor response may be partially linked to uncoupling cell surface message reception and nuclear gene expression, as well as recruitment of the innate immune system, disease progression and/or resistance may involve a reprogrammable signaling mainframe that elicits alternative growth and survival signals. This review attempts to meld current perceptions related to HER2-positive metastatic breast cancer with particular attention to current biological insights and therapeutic challenges.

ERBB4 Drives the Proliferation of BRAF-WT Melanoma Cell Lines

“…Hence, RTK overexpression, ligand overexpression, and gain-of-function mutations in an RTK gene are all mechanisms for pathologic, elevated RTK signaling [7]. Indeed, EGFR and ERBB2 have been validated as targets for therapeutic intervention in numerous types of tumors; monoclonal antibodies and small molecular tyrosine kinase inhibitors have been approved to treat tumors dependent on these receptors [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]. It appears that ERBB3, particularly ERBB3-ERBB2 heterodimers, also drives various human tumors [24,25].…”

Comparative Assessment of Quantification Methods for Tumor Tissue Phosphoproteomics

“… 4 Although these therapies significantly improve the survival rates, e.g., in breast cancer and leukemia, they suffer from significant initial and acquired resistance. 5 − 7 For most cancers and kinase-directed drug therapies reliable predictive markers of initial drug response and acquired resistance are largely missing. Pathway analysis in cancer cell lines highlights the potential to predict drug sensitivity 8 and calls for translation to patient tumor tissues.…”

“…Toward personalized treatments, genome and transcriptome analysis based detection of somatic mutations and mRNA changes has led to breakthroughs such as the identification of HER2-positivity that guides therapies with HER-targeting antibodies , or BCR-ABL fusion indicating a response to imatinib and its analogues . Although these therapies significantly improve the survival rates, e.g., in breast cancer and leukemia, they suffer from significant initial and acquired resistance. − For most cancers and kinase-directed drug therapies reliable predictive markers of initial drug response and acquired resistance are largely missing. Pathway analysis in cancer cell lines highlights the potential to predict drug sensitivity and calls for translation to patient tumor tissues.…”

Comparative assessment of quantification methods for tumor tissue phosphoproteomics

“…Although these therapies significantly improve the survival rates e.g. in breast cancer and leukemia, they suffer from significant initial and acquired resistance [5][6][7] . For most cancers and kinase-directed drug therapies reliable predictive markers of initial drug response and acquired resistance are largely missing.…”