Our study supports the importance of accurate patient stratification and rational drug combinations to gain benefit from MEK inhibition in patients with KRAS mutant NSCLC.
Our data show that combined targeting of MEK and PI3K-AKT with mTOR is a better option than single agents alone for KRAS mutant NSCLC, thus opening the possibility of a beneficial treatment strategy in the future.
There were statistically significant associations between high MEK (<i>P</i> = 0.028) and RAS (<i>P</i> = 0.003) signature scores and <i>KRAS</i> mutation in 50 NSCLC samples.
This finding suggests that, the combination of a MEK inhibitor with a BRAF inhibitor will be more efficacious in the clinical setting for patients with BRAF mutated NSCLC.
In line with the striking results observed in metastatic melanoma harboring the same molecular alteration, BRAF and MEK inhibition should be considered a new standard of care in this molecular subtype of NSCLC.
Targeted drugs against BRAF and downstream MEK were recently approved for the treatment of BRAF-positive melanoma and have entered clinical evaluation in NSCLC.
Moreover, in a mouse xenograft model, the combination of belinostat and trametinib significantly decreases tumor formation through FOXOs by increasing BIM and the cell-cycle inhibitors p21<sup>Cip1</sup> and p27<sup>Kip1</sup> These results demonstrate that control of FOXOs localization and expression is critical in <i>RAS</i>-driven lung cancer cells, suggesting that the dual molecular-targeted therapy for MEK and HDACs may be promising as novel therapeutic strategy in NSCLC with specific populations of <i>RAS</i> mutations.<i></i>.
<b>Purpose:</b> The MEK inhibitor trametinib radiosensitizes KRAS-mutant non-small cell lung cancer (NSCLC) and is being tested clinically with chemoradiation.
Although several groups have demonstrated that concomitant use of MEK and phosphoinositide 3-kinase (PI3K) inhibitors (MEKi/PI3Ki) can induce dramatic tumor regressions in mouse models of KRAS-mutant non-small cell lung cancer (NSCLC), ongoing clinical trials investigating this strategy have been underwhelming to date.
Blockade of α7 nicotinic acetylcholine receptors inhibit nicotine-induced tumor growth and vimentin expression in non-small cell lung cancer through MEK/ERK signaling way.
In this issue of <i>Cancer Research</i>, Xie and colleagues reveal an unexpected synergy between MEK inhibitors and immune checkpoint blockade in non-small cell lung cancer (NSCLC).
KRAS is the most frequent oncogene in non-small cell lung cancer (NSCLC), a molecular subset characterized by historical disappointments in targeted treatment approaches such as farnesyl transferase inhibition, downstream MEK inhibition, and synthetic lethality screens.
In conclusion, LncRNA BC087858 could promote cells invasion and induce non-T790M mutation acquired resistance to EGFR-TKIs by activating PI3K/AKT and MEK/ERK pathways and EMT via up- regulating ZEB1 and Snail in NSCLC.
Our findings indicate that the MAPK pathway is biologically important for MET-amplified NSCLC and strongly encourage the development of combination therapy with a MET inhibitor and a MEK inhibitor against MET-amplified NSCLC.
We demonstrate that <i>KRAS</i>-mutant NSCLC cell lines are initially sensitive to the CDK4/6 inhibitor palbociclib, but readily acquire resistance associated with increased expression of CDK6, D-type cyclins and cyclin E. Resistant cells also demonstrated increased ERK1/2 activity and sensitivity to MEK and ERK inhibitors.
Our findings that both EML4-ALK and mutant EGFR upregulate PD-L1 by activating PI3K-AKT and MEK-ERK signaling pathways in NSCLC reveal a direct link between oncogenic drivers and PD-L1 expression.
KRAS is one of the driver oncogenes in non-small-cell lung cancer (NSCLC) but remains refractory to current modalities of targeted pathway inhibition, which include inhibiting downstream kinase MEK to circumvent KRAS activation.