Editors' ChoiceCancer

EGFR Mutations Transform Tumors Inside and Out

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Science Translational Medicine  09 Oct 2013:
Vol. 5, Issue 206, pp. 206ec165
DOI: 10.1126/scitranslmed.3007712

Two unique approaches are redefining the treatment of advanced lung cancer: therapies that target mutated cellular kinases and, more recently, therapies that engage the immune system. Tyrosine kinase inhibitors (TKIs) like erlotinib and gefitinib target mutations in epidermal growth factor receptor (EGFR) that drive tumor cell signaling, growth, and proliferation. On the other hand, programmed death–1 (PD-1) blocking antibodies work outside of the tumor cell by interfering with a key inhibitory step in T cell activation in the tumor microenvironment. Akbay and colleagues connect these two approaches by presenting new evidence that EGFR mutations may be important both inside and outside of lung cancer cells.

The authors used mouse models of EGFR mutant lung cancer to describe the microenvironment associated with the tumors and compare it with normal lung tissue. They found that expression of PD-L1, the ligand for PD-1, on tumor and nontumor cells is a hallmark of the tumor microenvironment. Next, the authors transfected mutant EGFR into human bronchial epithelial cells in vitro. They found that EGFR signaling increases PD-L1expression in vitro and that PD-L1 expression can be reduced by treating EGFR mutant cell lines with TKIs. Last, the authors made the intriguing observation that, in the mouse models tested, EGFR mutant tumors are susceptible to PD-1 blockade, whereas KRAS mutant tumors are not. Because both the EGFR mutant and the KRAS mutant tumors in mice express PD-L1, additional factors appear likely to influence this process.

This work highlights the impact of the EGFR pathway both inside and outside of the cancer cell. Additional work will be needed to better understand how PD-L1 expression, immune cell phenotype, and tumor microenvironment may relate to the presence or absence of an EGFR mutation in human tumors. Therapeutic implications for the combination of TKIs and PD-1 blockade also remain to be explored.

E. A. Akbay et al., Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discov., published online 27 September 2013. (10.1158/2159-8290.CD-13-0310). [Full Text]

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