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

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Clinical cancer genome sequencing identifies numerous variants of unknown significance.
• Interactions between these variants and their impact on tumor pathophysiology remain largely unelucidated.
• The therapeutic implications of variants of unknown significance are unclear.

Purpose of the Study:

• To investigate the biological functions of the HER2 G776S mutation in colorectal cancer (CRC).
• To determine the oncogenic potential of the HER2 G776S mutation, particularly in conjunction with APC mutations.
• To evaluate the efficacy of afatinib as a targeted therapy for CRC with the HER2 G776S mutation.

Main Methods:

• Cancer genome sequencing of CRC patient samples.
• Transfection of the HER2 G776S mutation in cell lines.
• Analysis of HER2 kinase activity, downstream signaling pathways (Wnt, RAS-GTP, ERK), and cell phenotype.
• Assessment of tumor growth in xenograft models treated with afatinib.

Main Results:

• The HER2 G776S mutation alone showed minimal increase in kinase activity and no significant impact on downstream signaling or cell phenotype.
• In the presence of APC loss, the HER2 G776S mutation exhibited strong oncogenic potential.
• APC loss enhanced Wnt pathway activity and RAS-GTP levels, leading to increased ERK phosphorylation triggered by HER2 G776S.
• Afatinib treatment suppressed tumor growth in xenografts derived from HER2 G776S-transfected CRC cells.

Conclusions:

• The HER2 G776S mutation requires concurrent APC loss to exert significant oncogenic effects in CRC.
• The combination of APC loss and HER2 G776S mutation activates oncogenic signaling pathways.
• Afatinib demonstrates potential as a targeted therapy for colorectal cancer harboring the HER2 G776S mutation.