Epidermal Growth Factor Receptor (EGFR) and KRAS are the most commonly mutated oncogenes in lung cancer. EGFR kinase domain mutations have been established as valid predictors of increased sensitivity to gefitinib (Iressa, AstraZeneca) and erlotinib (Tarceva, Genentech). On the other hand, patients with mutant KRAS tumors fail to benefit from adjuvant chemotherapy and their disease does not respond to EGFR inhibitors.

Exciting research was presented during the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO) on the promising evidence of efficacy of selumetinib (AZD6244) which inhibits mitogen-activated protein kinase kinases (MEK or MAPK/ERK kinases) 1 and 2 and may prevent the activation of MEK1/2-dependent effector proteins and transcription factors inhibiting cellular proliferation in MEK-overexpressing tumor cells.

KRAS mutation-positive patients
While KRAS mutations are the most common mutation seen in lung cancer (and across different histologies) there is no effective treatment specifically for KRAS mutation-positive patients. Treatment with MEK inhibitors are quite promising.

Now, for the first time, Scientists have identified biomarkers that may help predict whether patients with KRAS-mutated non-small cell lung cancer (NSCLC) will respond to concurrent treatment with an MEK inhibitor and a PI3 kinase inhibitor, a drug combination currently being investigated in ongoing clinical trials. The data was presented during the Annual Meeting of the American Association for Cancer Research (AACR), held in Washington, D.C., April 6-10,, 2013 by Aaron N. Hata, M.D., Ph.D., a clinical fellow at the Massachusetts General Hospital in Boston.


Although several targeted therapies have been developed for patients with NSCLC, there are currently no proven targeted treatments for patients with NSCLC that harbors a KRAS mutation, which accounts for 20 to 25% of all NSCLC cases. ?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 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.?

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Apoptosis important response to of cancer therapy
To explore response to MEK and PI3 kinase inhibitors, Hata and colleagues studied a variety of NSCLC cell lines that all had mutated KRAS. They found that some of the cancer cell lines responded to the drug combination by undergoing a process of cell death called apoptosis, whereas others did not. ?Our results were not surprising from the standpoint that induction of cell death is known to be important for response of cancer cells to therapy,? Hata said. ?What was surprising was the difference in apoptosis among the cell lines.?

Decreased expression of pro-cell death mediators
Specifically, lack of a cell death response to the combination of MEK and PI3 kinase inhibitors correlated with the decreased expression of pro-cell death mediators and the upregulation of anti-cell death regulators. ?We found that three specific proteins predicted response,? Hata said. ?Two of them, the BIM and PUMA proteins, induced cell death, and the third, the BCL-XL protein, inhibited cell death.?

In addition, prior research has shown that many KRAS-mutant lung cancers also have a mutation in the TP53 gene, and the protein that it generates, P53, is known to be involved in the cell death process. In this study, the researchers found that TP53 mutation status did not predict response to the MEK/PI3 kinase inhibitor combination, but it did affect how the cells underwent cell death. ?Our research so far has focused on human cancer cell lines,? Hata said. ?We do not yet know if these correlations will hold true in patients.?

Measuring levels of protein
Ideally, Hata and his colleagues would like to determine whether the proteins they identified are predictive of patient response to MEK/PI3 kinase inhibitors in the clinic. ?The ultimate goal would be having the ability to measure levels of these proteins in patients before they go on treatment,? 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.?

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