In KRAS-Mutant Non-Small Cell Lung Cancer, Biomarkers May Predict Sensitivity to Combined MEK/PI3K Inhibition

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(ChemotherapyAdvisor) – Newly identified biomarkers may predict sensitivity to combined MEK and PI3K inhibition in patients with KRAS-mutant non-small cell lung cancer (NSCLC), results of a preclinical study presented at the American Association for Cancer Research (AACR) Annual Meeting 2013 in Washington, DC, has found.

Targeted therapies have been developed for NSCLC with activating epidermal growth factor receptor (EGFR) mutations or the EML4-ALK translocation, Aaron N. Hata, MD, PhD, a clinical fellow at the Massachusetts General Hospital in Boston, and colleagues noted; however, no highly effective targeted therapies exist for cancers harboring activating KRAS mutations, which represents 20% to 25% all cases of NSCLC.

“Treatment with an MEK inhibitor and PI3 kinase inhibitor is a combination targeted therapy that may be effective for some patients with KRAS-mutant NSCLC, but it is not likely to be effective for all patients with this form of cancer,” said Dr. Hata. “We want to be able to know which patients are going to respond to this combination therapy so that we can identify them and tailor their treatment accordingly.”

The investigators studied a variety of NSCLC cell lines, all of which had mutant KRAS. They found that human KRAS mutant NSCLC cell lines exhibited variability in responsiveness to MEKi/PI3Ki; next identified were key pro- and anti-apoptotic regulators of the apoptotic response induced by MEKi/PI3Ki.

“Loss of the apoptotic response due to down-regulation of pro-apoptotic mediators was associated with acquired resistance to MEK inhibitors (MEKi)/PI3K inhibitors (PI3Ki),” they noted, whereas “responsiveness of KRAS mutant NSCLCs to combined MEKi/PI3Ki could be predicted by the relative expression levels of specific apoptotic regulators, depending on TP53 mutational status.”

Three specific proteins predicted response: BIM- and PUMA-induced cell death and BCL-XL inhibited cell death. “These results reveal genotype-specific mechanisms of apoptosis necessary for responsiveness to targeted therapies and suggest biomarkers for predicting responsiveness of KRAS mutant NSCLC to MEKi/PI3Ki,” Dr. Hata noted.

“Our research so far has focused on human cancer cell lines,” he added. “We do not yet know if these correlations will hold true in patients.” Whether the proteins identified are predictive of patient response to MEK/PI3 kinase inhibitors in the clinic is a next step.

“The ultimate goal would be having the ability to measure levels of these proteins in patients before they go on treatment,” Dr. Hata said. “If they have favorable levels, that would tell us they are likely to respond to this treatment, and if they do not, it would be better to select a different treatment.”

The MEK/PI3K kinase inhibitor combination is currently being investigated in clinical trials.

Abstract #1137

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