2024 World Conference on Lung Cancer (WCLC) - Posters-P3.03I.02 Co-Inhibition of MEK/RTK Pathways Induces High Therapeutic Efficacy in Pan-KRAS-Mutant Non-Small Cell Lung Cancer

P3.03I.02 Co-Inhibition of MEK/RTK Pathways Induces High Therapeutic Efficacy in Pan-KRAS-Mutant Non-Small Cell Lung Cancer

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Dr. Jun Lu and colleagues from the Shanghai Chest Hospital conducted a study to address the challenges of treating KRAS-mutant non-small cell lung cancer (NSCLC), a common but difficult-to-target mutation in lung cancer. MEK inhibitors, such as trametinib, are potential treatments for KRAS-mutant NSCLC, but patients often develop resistance, primarily due to the activation of receptor tyrosine kinases (RTKs) as a feedback mechanism.<br /><br />The study explored a combination therapy of MEK inhibition with trametinib and RTK inhibition using anlotinib. This dual-inhibition strategy aimed to overcome adaptive resistance and offer a more effective treatment for KRAS-mutant cancers. In their research, the team tested this combination on NSCLC patients with various KRAS mutations, such as KRASG12D, KRASG12F, KRASG12C, KRASQ61H, and KRASG12V.<br /><br />Results showed that trametinib treatment alone led to the activation of multiple RTKs, promoting resistance via the ERK/AKT signaling pathway. However, combining trametinib with anlotinib effectively inhibited this pathway, suppressing cancer progression. The study suggests that the combination works synergistically by involving a feedback loop with IGFBP2, a protein demonstrating significant anti-tumor efficacy.<br /><br />Animal models, as well as clinical trials with five advanced NSCLC patients carrying different KRAS mutations, confirmed the potential of this combinatorial approach. Dr. Lu's findings point to a promising strategy that targets both MEK and RTK pathways, achieving better therapeutic outcomes for patients with pan-KRAS-mutant NSCLC. This research provides new insights into overcoming drug resistance in KRAS-mutant cases and may guide future cancer treatment protocols.

Asset Subtitle

Jun Lu

Meta Tag

Speaker Jun Lu

Topic Tumor Biology – Translational Biology

Keywords

KRAS-mutant NSCLC

MEK inhibitors

trametinib

RTK inhibition

anlotinib

adaptive resistance

ERK/AKT pathway

IGFBP2

combination therapy

lung cancer treatment