EACR25-0351

Acquisition of resistance to targeted therapies in lung cancer: mechanistic basis and suppressive strategies

J. Guimarães¹, S. Junqueira-Neto², M. Fernandes², C. Resende², A. Vilarinho², J. Pinheiro³, C. Souto-Moura⁴, S. Melo², J. Costa², J. Machado²

¹i3S, Intercellular Communication and Cancer, Porto, Portugal
²i3S, ntercellular Communication and Cancer, Porto, Portugal
³i3S, Ipatimup Diagnostics, Porto, Portugal
⁴FMUP, Departamento de Patologia, Porto, Portugal

Introduction:

Targeted cancer therapies efficiently reduce tumor growth and progression. However, the development of resistance unavoidably occurs, representing a major cause of cancer-related deaths. Despite being the triggering event, we have demonstrated that the resistance mutation is present only in a fraction of relapsing tumor cells, evidencing that the resistance phenotype can be transferred among cancer cells. This challenges the prevailing view of resistance development based solely on cell division and selection of mutated cells.

Material and method:

We used the human H1975 EGFRp.L858R/EGFRp.T790M Erlotinib-resistant and HCC827 EGFRp.delE746-A750 Erlotinib-sensitive lung cancer cell lines both in vitro and in a co-inoculation immunodeficient C57BL/6[-/-]; Il2rg[-/-] mouse model to study the transcriptomic, proteomic and epigenetic profile of therapy sensitive cells before and after development of resistance. This approach aimed to evaluate the impact of the stimulus from the resistant cell line on the acquisition of resistance in sensitive cells and investigate the stability of the acquired phenotypic resistance

Result and discussion:

We showed that supplementation with conditioned medium from therapy-resistant cells, as well as dual inoculation of sensitive and resistant cells in our mouse model, leads to a faster and more stable resistance phenotype. In addition, the acquisition of resistance triggers a change in the transcriptional landscape, characterized by the enrichment of the endocytosis pathway, specifically through Caveolin-1 overexpression, which we further validated in human samples. Downstream pathway analysis has identified PI3K as a potential effector of resistance, whose inhibition can restore sensitivity to therapy as well as novel evidence regarding the role of AKT and ERK in cell survival and resistance to therapy. The methylation array analysis revealed that the therapy-resistant phenotype acquired appears to be accompanied by an epithelial-to-mesenchymal transition (EMT) through known mediators such as STK26.

Conclusion:

These findings suggest that resistance can arise through alternative mechanisms, potentially influenced by interactions between cancer cells and underscore the complexity of resistance mechanisms, highlighting the potential of targeting intercellular communication to overcome resistance in lung cancer therapy.