Scientific Reports (Jun 2022)

HER2 G776S mutation promotes oncogenic potential in colorectal cancer cells when accompanied by loss of APC function

  • Yosuke Mitani,
  • Shinya Ohashi,
  • Osamu Kikuchi,
  • Yukie Nakai,
  • Tomomi Ida,
  • Ayaka Mizumoto,
  • Yoshihiro Yamamoto,
  • Tomoki Saito,
  • Shigeki Kataoka,
  • Junichi Matsubara,
  • Atsushi Yamada,
  • Masashi Kanai,
  • Shigemi Matsumoto,
  • Hiroaki Sakai,
  • Kiyotsugu Yoshikawa,
  • Eijiro Nakamura,
  • Manabu Muto

DOI
https://doi.org/10.1038/s41598-022-13189-y
Journal volume & issue
Vol. 12, no. 1
pp. 1 – 15

Abstract

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Abstract Clinical cancer genome sequencing detects oncogenic variants that are potential targets for cancer treatment, but it also detects variants of unknown significance. These variants may interact with each other to influence tumor pathophysiology, however, such interactions have not been fully elucidated. Additionally, the effect of target therapy for those variants also unclarified. In this study, we investigated the biological functions of a HER2 mutation (G776S mutation) of unknown pathological significance, which was detected together with APC mutation by cancer genome sequencing of samples from a colorectal cancer (CRC) patient. Transfection of the HER2 G776S mutation alone slightly increased the kinase activity and phosphorylation of HER2 protein, but did not activate HER2 downstream signaling or alter the cell phenotype. On the other hand, the HER2 G776S mutation was shown to have strong oncogenic potential when loss of APC function was accompanied. We revealed that loss of APC function increased Wnt pathway activity but also increased RAS–GTP, which increased ERK phosphorylation triggered by HER2 G776S transfection. In addition, afatinib, a pan-HER tyrosine kinase inhibitor, suppressed tumor growth in xenografts derived from HER2 G776S-transfected CRC cells. These findings suggest that this HER2 mutation in CRC may be a potential therapeutic target.