The potential therapeutic regimen for overcoming resistance to osimertinib due to rare mutations in NSCLC

Han, Rui; Lin, Caiyu; Zhang, Chong; Kang, Jun; Lu, Conghua; Zhang, Yiming; Wang, Yübo; Hu, Chen; He, Yong

doi:10.1016/j.isci.2023.107105

Cited by 1 publication

(1 citation statement)

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“…35 36 The current state of managing TKI resistance is problematic, and while new generations of targeted drugs are in clinical trials, 37 they only solve the issue for a small portion of resistant patients. 38 A more practical solution may lie in enhancing our understanding of resistance mechanisms and achieving prolonged use of existing targeted drugs without the onset of resistance. Our previous research has already demonstrated that an immunologically active TME is the reason for the pathological remission and better prognosis obtained with immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

Understanding the dynamics of TKI-induced changes in the tumor immune microenvironment for improved therapeutic effect

Lu,

Gao,

et al. 2024

J Immunother Cancer

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BackgroundThe dynamic interplay between tyrosine kinase inhibitors (TKIs) and the tumor immune microenvironment (TME) plays a crucial role in the therapeutic trajectory of non-small cell lung cancer (NSCLC). Understanding the functional dynamics and resistance mechanisms of TKIs is essential for advancing the treatment of NSCLC.MethodsThis study assessed the effects of short-term and long-term TKI treatments on the TME in NSCLC, particularly targeting epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations. We analyzed changes in immune cell composition, cytokine profiles, and key proteins involved in immune evasion, such as laminin subunit γ−2 (LAMC2). We also explored the use of aspirin as an adjunct therapy to modulate the TME and counteract TKI resistance.ResultsShort-term TKI treatment enhanced T cell-mediated tumor clearance, reduced immunosuppressive M2 macrophage infiltration, and downregulated LAMC2 expression. Conversely, long-term TKI treatment fostered an immunosuppressive TME, contributing to drug resistance and promoting immune escape. Differential responses were observed among various oncogenic mutations, with ALK-targeted therapies eliciting a stronger antitumor immune response compared with EGFR-targeted therapies. Notably, we found that aspirin has potential in overcoming TKI resistance by modulating the TME and enhancing T cell-mediated tumor clearance.ConclusionsThese findings offer new insights into the dynamics of TKI-induced changes in the TME, improving our understanding of NSCLC challenges. The study underscores the critical role of the TME in TKI resistance and suggests that adjunct therapies, like aspirin, may provide new strategies to enhance TKI efficacy and overcome resistance.

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Section: Discussionmentioning

confidence: 99%