Alternative Treatment Options to ALK Inhibitor Monotherapy for EML4-ALK-Driven Lung Cancer

Abstract

EML4-ALK is an oncogenic fusion protein that accounts for approximately 5% of NSCLC cases. Targeted inhibitors of ALK are the standard of care treatment, often leading to a good initial response. Sadly, some patients do not respond well, and most will develop resistance over time, emphasizing the need for alternative treatments. This review discusses recent advances in our understanding of the mechanisms behind EML4-ALK-driven NSCLC progression and the opportunities they present for alternative treatment options to ALK inhibitor monotherapy. Targeting ALK-dependent signalling pathways can overcome resistance that has developed due to mutations in the ALK catalytic domain, as well as through activation of bypass mechanisms that utilise the same pathways. We also consider evidence for polytherapy approaches that combine targeted inhibition of these pathways with ALK inhibitors. Lastly, we review combination approaches that use targeted inhibitors of ALK together with chemotherapy, radiotherapy or immunotherapy. Throughout this article, we highlight the importance of alternative breakpoints in the EML4 gene that result in the generation of distinct EML4-ALK variants with different biological and pathological properties and consider monotherapy and polytherapy approaches that may be selective to particular variants.

Breaking paradigms: Long non-coding RNAs forming gene fusions with potential implications in cancer

“…Of all the fusion lncRNAs we described in the previous section, it is really exciting to appreciate all the fusions in which PVT1 is involved, as it reminds us of the famous EML4–ALK gene fusion detected in anaplastic lymphoma and non-small cell lung cancer; despite its low prevalence, there are several drugs to inhibit its kinase activity, thus representing a watershed in therapeutics. 108 , 109 These findings allow us to speculate that there is an emerging window of opportunity for further analysis of PVT1-generated fusions. However, the scenario becomes more lurid if PVT1 fusions are not translated into protein.…”

Mitoxantrone and abacavir: An ALK protein-targeted in silico proposal for the treatment of non-small cell lung cancer

“…Despite the existence of iALKs for ALK + NSCLC patients, resistance to iALKs has been seen across disease progression. Resistance to crizotinib, ceritinib, brigatinib, alectinib, and lorlatinib is produced by specific mutations in the ATP-binding site [ 35 ]. Therefore, understanding the cdALK + -iALK interaction allows us to propose molecules and/or drugs with potential pharmacological repositioning capacity.…”

The Role of mTOR in B Cell Lymphoid Malignancies: Biologic and Therapeutic Aspects

“…Meanwhile, other potential combinations either gained approval (polatuzumab vedotin) or were intensively evaluated in phase III studies (epcoritamab, tafasitamab plus lenalidomide, etc.) in combination with R-CHOP with or without vincristine [ 92 ]. The adjuvant use of everolimus as maintenance after chemoimmunotherapy was not beneficial overall in the PILLAR-2 study [ 87 ].…”