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.
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.
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.
Therefore, combinatorial therapy with osimertinib and a MET or even a MEK inhibitor should be considered for these patients with resistant NSCLC carrying MET amplification and/or protein hyperactivation.
We studied the effects of MEK inhibitors (MEK-I) on PD-L1 and MCH-I protein expression and cytokine production in vitro in NSCLC cell lines and in PBMCs from healthy donors and NSCLC patients, the efficacy of combining MEK-I with anti-PD-L1 antibody in ex-vivo human spheroid cultures obtained from fresh biopsies from NSCLC patients in terms of cell growth arrest, cytokine production and T-cell activation by flow cytometry.
Real-life comparative data on BRAF inhibitors (BRAFi) and BRAFi + MEK inhibitors (MEKi) combination in BRAF-mutant (BRAFm) non-small-cell lung cancer (NSCLC) is lacking.
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.
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.
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.
Finally, simultaneous genetic silencing of <i>RASA1</i> and <i>NF1</i> sensitized both HBECs and NSCLC cells to MEK inhibition.<b>Conclusions:</b> Cancer genomic and functional data nominate concurrent <i>RASA1/NF1</i> loss-of-function mutations as a strong mitogenic driver in NSCLC, which may sensitize to trametinib.<i>Clin Cancer Res; 24(6); 1436-47.
In conclusion, our results indicate that the combined therapy using MEK and PI3K inhibitors is a potent therapeutic strategy for NSCLC with the acquired resistance to EGFR-TKIs.
In this article, we discuss the biological rationale for the use of MEK inhibitors and summarize the clinical experience with MEK1/2 inhibitors for the treatment of NSCLC, from initial phase I studies to phase II/III studies, both as monotherapy or in combination with other anticancer agents.
We discover a novel strategy for integrating BCL-xL and MCL1 inhibitors to drive and subsequently exploit apoptotic dependencies of <i>KRAS</i>-mutant NSCLCs treated with MEK inhibitors.<i>See related commentary by Leber et al., p. 1511</i>.<i>This article is highlighted in the In This Issue feature, p. 1494</i>.
Here we demonstrated that a combination of MEK and BRAF inhibitors overcomes paradoxical MAPK activation (induced by BRAF inhibitors) in BRAF-wt/RAS-mut NSCLC and PDAC in vitro.
Synergy was observed when both SHP2 and MEK were targeted, resulting in sustained tumor growth control in murine and human patient-derived organoids and xenograft models of pancreatic ductal adenocarcinoma and non-small-cell lung cancer.
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.