HER2 expression and PI3K-Akt pathway alterations in gastric cancer.
The anti-HER2 antibody trastuzumab has led to an era of personalized therapy in gastric cancer (GC). As a result, HER2 expression has become a major concern in GC. HER2 overexpression is seen in 7-34% of GC cases. Trastuzumab is an antibody that targets the HER2 extracellular domain and induces antibody-dependent cellular cytotoxicity and inhibition of the HER2 downstream signals. Mechanisms of resistance to trastuzumab have been reported in breast cancer. There are various mechanisms underlying trastuzumab resistance, such as alterations of HER2 structure or surroundings, dysregulation of HER2 downstream signal effectors and interaction of HER2 with other membrane receptors. The PI3K-Akt pathway is one of the main downstream signaling pathways of HER2. It is well known that PIK3CA mutations and phosphate and tensin homolog (PTEN) inactivation cause over-activation of the downstream signal without an upstream signal activation. Frequencies of PIK3CA mutations and PTEN inactivation have been reported to be 4-25 and 16-77%, respectively. However, little is known about the association between HER2 expression and PI3K-Akt pathway alterations in GC. We have found that HER2 over-expression was significantly correlated with pAkt expression in GC tissues. Furthermore, pAkt expression was correlated with poor prognosis. These results suggest that the PI3K-Akt pathway plays an important role in HER2-positive GC. Moreover, PIK3CA mutations and/or PTEN inactivation might affect the effectiveness of HER2-targeting therapy. Hence, it is necessary to clarify not only HER2 alterations but also PI3K-Akt pathway alterations for HER2-targeting therapy in GC. This review will introduce recent investigations and consider the current status of HER2-targeted therapy for treatment of GC.
Department of Gastroenterology, Rheumatology and Clinical Immunology Sapporo Medical University School of Medicine, Sapporo, Japan.
Yasutaka
Y
Sukawa
Hiroyuki
H
Yamamoto
Katsuhiko
K
Nosho
Miki
M
Ito
Hisayoshi
H
Igarashi
Takafumi
T
Naito
Kei
K
Mitsuhashi
Yasutaka
Y
Matsunaga
Taiga
T
Takahashi
Masashi
M
Mikami
Yasushi
Y
Adachi
Hiromu
H
Suzuki
Yasuhisa
Y
Shinomura
D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000276:immunology; D006801:Humans; D009154:Mutation; D058539:Phosphatidylinositol 3-Kinase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction / Q000502:physiology*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D000068878:Trastuzumab
D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human