Heterogeneous ERBB gene pathways, their targeted treatment and possible molecular mechanisms of resistance in metastatic gallbladder cancer.

Background: ERBB amplifications and mutations are known in metastatic gallbladder cancer (GBC). We conducted a prospective study on targeted therapy based on comprehensive genomic profiling (CGP). We report molecular pathways of ERBB gene and outcomes and explored the molecular mechanism of resistance. Methods: CGP was done for all consecutive GBC patients aged >18 years. Foundation medicines CDx and TarGT Absolute were used for analysis. Patients were enrolled from Jan 2017 till Dec 2022. Patient recruitment was done after ethics committee approval. Trastuzumab and/ or lapatinib were used as targeted therapy. Results: Twenty-six patients out of 60 had ERBB1-4 gene alteration (amplification and/or mutation) that resulted in activation of PI3K/AKT/MTOR and RAS/RAF/MEK pathways. ERBB amplification (16%) was the most common genetic aberration. Mutations in TP53, RB1, CDKs, and cyclins lead to dysregulation of cell cycle and evasion of apoptosis. A total of 50% of ERBB2-positive patients carry CDK12 amplifications. The intrinsic resistance to anti-ERBB2 therapy was primarily due to downstream activation in ERBB pathway (PIK3CA) and its crosstalk with cell cycle pathway (TP53 and CDK12), JAK/STAT, VEGF, CTNNB1, and ARID1A that are known to drive MAPK/ERK signaling. Mesenchymal epithelial transition amplification or activating mutations is mechanism of resistance to anti-ERBB2 therapy. Kinase/Juxta membrane domain mutations in ERBB family proteins are also one of the potential mechanisms of resistance. Conclusion: GBC is enriched with ERBB gene aberrations. Targeted therapy of ERBB pathway has shown encouraging responses. CDK12 gene amplification is a possible mechanism of resistance identified. CTRI Registration no: CTRI/2020/05/025147.