KRAS mutant lung cancer cells responding to targeted drug treatments.

KRAS Mutant Lung Cancer: How Targeted Treatments Impact PD-L1 Expression

Soraya Malik in Health & Wellness December 2025 • 4 min read.

"New research explores how MEK and AKT inhibitors affect PD-L1 in KRAS mutant lung cancer cells, offering insights into treatment resistance and immune response."

Lung cancer remains a leading cause of cancer-related deaths worldwide, with nearly 1.8 million new diagnoses each year. While standard treatments for metastatic non-small cell lung cancer (NSCLC) have evolved to include targeted therapies like EGFR and ALK inhibitors, as well as immune checkpoint inhibitors, challenges persist, particularly in specific genetic subsets of the disease.

Programmed death-ligand 1 (PD-L1) is a crucial protein that interacts with PD-1 receptors on T-cells, playing a vital role in regulating immune responses. Inhibitors targeting the PD-1/PD-L1 pathway have demonstrated significant benefits in treating both squamous and adenocarcinoma types of lung cancer, highlighting the potential of immunotherapies.

KRAS mutations are present in approximately 33% of advanced lung adenocarcinomas. Currently, there are no approved drugs that directly inhibit KRAS. Researchers are exploring the use of MEK and AKT inhibitors, but their efficacy as single agents has been limited. Recent investigations suggest that combining these inhibitors may yield more promising results.

Decoding the Impact of MEK and AKT Inhibitors on PD-L1

KRAS mutant lung cancer cells responding to targeted drug treatments.

A recent study investigated how KRAS mutant lung cancer cells respond to MEK and AKT inhibitors, focusing on changes in PD-L1 expression. The study used immunofluorescence to quantify PD-L1 levels and co-cultured cancer cell lines with Jurkat cells to assess the functional relevance of PD-L1 changes. Five KRAS mutant cell lines with initially high PD-L1 expression—H441, H2291, H23, H2030, and A549—were treated with GI50 concentrations of trametinib (MEK inhibitor) and AZD5363 (AKT inhibitor) for three weeks.

The results indicated varied responses across the cell lines. When exposed to trametinib:

H23, H2030, and A549 showed increased PD-L1 expression.
H441 exhibited a decrease in PD-L1 expression.
H2291 showed no significant change.

Exposure to AZD5363 resulted in:

Increased PD-L1 expression in H441 and H23.
Reduced PD-L1 expression in H2291 and A549.

These findings suggest that PD-L1 overexpression is not a consistent response to MEK or AKT inhibitors in KRAS mutant lung adenocarcinoma.

These inconsistencies suggest that PD-L1 overexpression is not a reliable early mechanism of resistance in KRAS mutant lung adenocarcinoma when treated with MEK or AKT inhibitors. The variable responses highlight the complexity of cellular signaling and the need for more refined therapeutic strategies.

Implications and Future Directions

This research provides a novel look into the effects of signaling pathway inhibitors on immune pathway interactions, highlighting small, inconsistent changes in PD-L1 levels across different cell lines. Further studies, potentially involving immunocompetent animal models, are needed to validate these findings and explore the functional relevance of PD-L1 expression as a mechanism of resistance. Integrating these insights could refine therapeutic strategies for KRAS mutant lung cancer, moving towards more personalized and effective treatments.

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Everything You Need To Know

What is the significance of PD-L1 in lung cancer and how do targeted therapies interact with it?

PD-L1 (Programmed death-ligand 1) is a protein that interacts with PD-1 receptors on T-cells, influencing immune responses. In lung cancer, particularly in the context of KRAS mutations, PD-L1 expression is crucial because it can affect the efficacy of immunotherapies. Targeted therapies, such as MEK and AKT inhibitors, can alter PD-L1 expression levels. The research indicates that the impact of these inhibitors on PD-L1 varies across different KRAS mutant lung cancer cell lines (H441, H2291, H23, H2030, and A549), suggesting a complex relationship between these treatments and the immune response. For example, trametinib (MEK inhibitor) increased PD-L1 in H23, H2030, and A549, while decreasing it in H441. This variability highlights the need for personalized therapeutic strategies.

How do MEK and AKT inhibitors influence PD-L1 expression in KRAS mutant lung cancer cells?

MEK and AKT inhibitors have different effects on PD-L1 expression depending on the specific KRAS mutant lung cancer cell line. The study used trametinib (MEK inhibitor) and AZD5363 (AKT inhibitor) on five cell lines: H441, H2291, H23, H2030, and A549. Trametinib increased PD-L1 expression in H23, H2030, and A549, decreased it in H441, and showed no change in H2291. AZD5363 increased PD-L1 in H441 and H23 and reduced it in H2291 and A549. These variable responses demonstrate that the effect of MEK and AKT inhibitors on PD-L1 is not uniform and suggests that PD-L1 overexpression is not a reliable indicator of resistance in these cancers.

What are the implications of the varied responses of KRAS mutant lung cancer cell lines to MEK and AKT inhibitors concerning treatment resistance?

The inconsistent responses of the KRAS mutant lung cancer cell lines (H441, H2291, H23, H2030, and A549) to MEK and AKT inhibitors have significant implications for understanding treatment resistance. The study found that PD-L1 expression changes were not consistent across different cell lines when exposed to trametinib (MEK inhibitor) and AZD5363 (AKT inhibitor). These variations indicate that PD-L1 overexpression is not a consistent early mechanism of resistance. This complexity underscores the need for more refined therapeutic strategies beyond simply targeting MEK or AKT. Furthermore, it highlights that resistance mechanisms are likely multifaceted and cell-line-specific, meaning that a treatment effective for one cell line might not work for another. This points to the necessity of personalized treatment approaches based on the specific genetic and molecular profiles of the tumor.

What are the limitations of the current research and what future directions are being explored?

The current research provides insights into how MEK and AKT inhibitors affect PD-L1 expression in KRAS mutant lung cancer cell lines (H441, H2291, H23, H2030, and A549). However, it has limitations. The study primarily focused on in-vitro cell lines. Further studies involving immunocompetent animal models are needed to validate these findings and fully understand the functional relevance of PD-L1 expression as a mechanism of resistance. Future directions involve exploring more refined therapeutic strategies and potentially integrating these findings to move towards more personalized and effective treatments for KRAS mutant lung cancer. The use of combination therapies and further investigation into the mechanisms driving resistance are key areas of focus.

Can MEK and AKT inhibitors be used to treat KRAS mutant lung cancer, and if so, how effective are they?

Currently, there are no approved drugs that directly inhibit KRAS. However, MEK and AKT inhibitors are being explored as potential treatment options. The efficacy of these inhibitors as single agents has been limited. Recent studies suggest that combining these inhibitors may yield more promising results. The research indicates that when using trametinib (MEK inhibitor) and AZD5363 (AKT inhibitor), responses vary across different KRAS mutant lung cancer cell lines (H441, H2291, H23, H2030, and A549). For instance, the changes in PD-L1 expression differ among these cell lines. The variability suggests the need for personalized treatment approaches and further research to determine the optimal use of these inhibitors in combination with other therapies. Their overall effectiveness is still under investigation, and it is likely that their role will be part of a broader, multi-faceted treatment strategy.