Potential Biomarkers Identified for Predicting Response to Drugs Targeting KRAS-Mutated NSCLC

Aaron N. Hata, MD, PhD

Preliminary in vitro analysis has identified markers that may predict response to drugs that target KRAS-mutated non—small cell lung cancer (NSCLC), but this work is preliminary and further study is needed, said researchers at the 2013 AACR Annual Meeting. The investigators identified three proteins that were able to predict response to treatment with a MEK inhibitor plus a PI3 kinase inhibitor—an investigational approach to NSCLC, including some KRAS-mutated cancers.

About 25% of all NSCLCs harbor a KRAS mutation, and currently there are no proven targeted therapies for such cases. There are, however, therapies targeted to cancers with activating EGFR mutations and ALK translocations. KRAS-mutated NSCLCs represent a heterogeneous group of cancers, and it is possible that the combination of a MEK inhibitor and PI3 kinase inhibitor may be effective for some forms of KRAS-mutated NSCLC, but not for all patients with this type of cancer, explained lead author Aaron N. Hata, MD, PhD, a clinical fellow at Massachusetts General Hospital in Boston. “We want to be able to identify which patients will respond to this combination therapy and tailor their treatment accordingly,” Hata told listeners.

Hata and colleagues studied a variety of NSCLC cell lines with mutated KRAS and evaluated response to MEK and PI3 kinase inhibitors. Some of the cell lines responded by undergoing apoptosis, while others did not.

“Our results were not surprising from the standpoint that induction of apoptosis is known to be an important element of response to cancer therapy. What was surprising was the difference in apoptosis among the cell lines,” he explained. Lack of apoptosis to the combination of MEK and PI3 kinase inhibitors correlated with the decreased expression of pro-cell death mediators and the upregulation of antiapoptotic regulators.

Three specific proteins predicted response: Bim and Puma proteins induced cell death, while Bcl-xl protein inhibited cell death. Prior research has established that many KRAS-mutant lung cancers also have a P53 mutation, and the P53 protein is involved in apoptosis. In this study, TP53 did not predict response to the investigational drug combination, but it did affect how the cells underwent apoptosis.

Hata acknowledged that this was early in vitro work, and that human studies are needed to explore whether the three proteins predict patients’ response to MEK and PI3 kinase inhibitors in the clinical setting.

“Ultimately, the goal would be to have the ability to measure the levels of these proteins before a patient is treated. If he or she had favorable levels, then this would predict a likely response; but if the levels are not favorable, that would suggest the need to try a different treatment,” Hata said.

Hata A, Faber A, Yeo A, et al. Expression of specific apoptotic mediators predicts sensitivity to combined MEK and PI3K inhibition in KRAS mutant non-small cell lung cancer according to TP53 mutational status. Presented at: the AACR Annual Meeting; April 6-10, 2013; Washington, DC. Abstract 1137.