Introduction: HER2-targeted therapies (monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs) and tyrosine kinase inhibitors (TKIs)) have greatly improved the outcome of patients with HER2-positive breast cancer (BC). However, many patients with HER2-positive lung, gastroesophageal or pancreatic cancer lack treatment options. This PhD project aimed to investigate the efficacy of the pan-HER TKI neratinib in HER-driven cancers outside of BC and to develop therapeutic strategies to treat those cancers and overcome potential resistance. Methods: The efficacy of neratinib alone and combinations of neratinib with inhibitors like dasatinib (multi-kinase), crizotinib (ALK) and sotorasib (KRASG12C) was investigated in vitro in HER-driven gastroesophageal, lung, pancreatic and head and neck cancer cell lines by proliferation, apoptosis, migration assays and signalling analysis. Neratinib-sotorasib was further evaluated in 3D spheroids and oesophageal xenografts. Neratinib was also investigated in 3D oesophageal organoids by viability assays. A CRISPR/Cas9 method was developed to insert a KRASG12C point mutation in two HER2-amplified cell lines to further investigate neratinib-sotorasib. Results: Neratinib had anti-proliferative effects in all the cell lines tested, particularly those with HER2 and/or EGFR amplification. Neratinib had anti-tumour efficacy in oesophageal organoid models. Neratinib-dasatinib showed efficacy in several lung, gastric and oesophageal cancer cell lines with HER2 and/or EGFR amplification. Neratinib-sotorasib was a potent combination in HER2-amplified, KRASG12C-mutated oesophageal and lung cancer cell lines in 2D and 3D. Both neratinib alone and neratinib-sotorasib led to tumour regression of oesophageal xenografts due to inhibited HER2 activity, with the combination inducing sustained tumour stabilisation after the treatment was stopped. The insertion of the KRASG12C mutation using CRISPR/Cas9 was not successful but novel cell lines with KRAS alterations were created. ALK alterations were identified as potentially mediating neratinib resistance. The combination neratinib-dasatinib-crizotinib augmented proliferation inhibition of an EML4-ALK fusion-harbouring lung cancer cell line, while dasatinib-crizotinib proved efficacious in a model of ALK- and c-MET-amplified gastric cancer. Conclusion: The findings of this thesis highlight the strong potential of neratinib-based targeted treatment strategies in subgroups of patients with cancer types outside BC.