Targeting treatment resistance in ALK-translocated NSCLC

Molecular identification of actionable targets and corresponding targeted therapies has revolutionized the treatment of non-small cell lung cancer (NSCLC) in the last decade and is now part of routine clinical practice. Although most patients respond to the targeted therapies, therapy resistance is an important issue. Acquired resistance develops in virtually all patients who initially respond to treatment, while primary resistance is rare but still an existing hurdle.

This thesis focused on the anaplastic lymphoma kinase (ALK) translocated NSCLC and its treatment with ALK targeted therapies using in vitro models. Furthermore, the molecular mechanisms underlying treatment resistance to ALK-targeted therapies and the therapeutic strategies to overcome it were explored. Regarding the treatment resistance mechanisms, the thesis focused on the role of the human epidermal growth factor receptor 3 (HER3). On the therapeutic side, the thesis explored the use of HER3-targeting small-molecule inhibitors and antibody-drug conjugate therapies. Furthermore, concurrent use of chemotherapy and ALK-TKIs was investigated to improve treatment outcomes.

The thesis showed that HER3 influences therapy resistance in ALK-translocated NSCLC and is a potential target for therapeutic intervention in the disease. Furthermore, the thesis provided evidence of ALK and HER3 interaction, linking it to altered downstream signaling. Lastly, the thesis demonstrated that chemotherapy and ALK-TKIs can exhibit synergistic effects, and that the therapeutic sequence plays a role in effectiveness.