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EGFR: The Paradigm of an Oncogene-Driven Lung Cancer.

ABSTRACT: Somatic, activating mutations in EGFR identify a significant minority of patients with non-small cell lung cancer (NSCLC). Although these mutations are associated with an approximately 70% response rate to some EGFR tyrosine kinase inhibitors (gefitinib, erlotinib, and afatinib), patients develop resistance (i.e., "acquired resistance") after a median of 9 to 12 months. In patients with clinical acquired resistance, repeat biopsy of tumors has identified a number of relevant mechanisms of resistance, but by far the most frequent event is the acquisition of EGFR T790M, a mutation in the "gatekeeper" residue that confers resistance to gefitinib, erlotinib, and afatinib. This emphasizes the critical dependence upon EGFR signaling for some tumors, a property that has been exploited therapeutically. Dual EGFR blockade using afatinib and cetuximab led to a 29% radiographic response rate. More recently, drugs that target EGFR T790M (e.g., rociletinib, AZD9291, and others) have entered clinical trials, with impressive results observed in phase I clinical trials. The development of these newer drugs, with efficacy after resistance to first-line EGFR tyrosine kinase inhibitor, has led to exploration of these strategies in multiple disease settings: at resistance, in the first line, and in adjuvant treatment of those with completely resected early-stage disease who would otherwise die of recurrent/metastatic disease. This example of translational research that identifies mechanisms of resistance to first-generation drugs, and then targets those mechanisms yielding clinical benefit, is a paradigm for how targeted therapies can be developed.

SUBMITTER: Riely GJ

PROVIDER: S-EPMC4435716 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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EGFR: The Paradigm of an Oncogene-Driven Lung Cancer.

Riely Gregory J GJ Yu Helena A HA

Clinical cancer research : an official journal of the American Association for Cancer Research 20150501 10

Somatic, activating mutations in EGFR identify a significant minority of patients with non-small cell lung cancer (NSCLC). Although these mutations are associated with an approximately 70% response rate to some EGFR tyrosine kinase inhibitors (gefitinib, erlotinib, and afatinib), patients develop resistance (i.e., "acquired resistance") after a median of 9 to 12 months. In patients with clinical acquired resistance, repeat biopsy of tumors has identified a number of relevant mechanisms of resist ...[more]

PMID: 25979928

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Project description:Simple Summary Lung cancer that is driven by mutations in the epidermal growth factor receptor (EGFR) is currently treated with tyrosine kinase inhibitors (TKIs). Although patients initially respond well to TKI treatment, drug resistance against EGFR-targeted therapy emerges. Attempts to combine immunotherapy with EGFR-targeted treatment to prolong response rates or prevent the development of resistances have been limited due to insufficient knowledge about the effects of targeted therapy on the tumour microenvironment (TME) in EGFR-driven tumours and tumour-infiltrating immune cells. The aims of this study were to improve our understanding on the impact of EGFR inhibition on the immune response in EGFR-driven lung cancer and, furthermore, to gain insights into the impact of combining targeted therapy with immunotherapy on the TME. Abstract EGFR-driven non-small-cell lung cancer (NSCLC) patients are currently treated with TKIs targeting EGFR, such as erlotinib or osimertinib. Despite a promising initial response to TKI treatment, most patients gain resistance to oncogene-targeted therapy, and tumours progress. With the development of inhibitors against immune checkpoints, such as PD-1, that mediate an immunosuppressive microenvironment, immunotherapy approaches attempt to restore a proinflammatory immune response in tumours. However, this strategy has shown only limited benefits in EGFR-driven NSCLC. Approaches combining EGFR inhibition with immunotherapy to stimulate the immune response and overcome resistance to therapy have been limited due to insufficient understanding about the effect of EGFR-targeting treatment on the immune cells in the TME. Here, we investigate the impact of EGFR inhibition by erlotinib on the TME and its effect on the antitumour response of the immune cell infiltrate. For this purpose, we used a transgenic conditional mouse model to study the immunological profile in EGFR-driven NSCLC tumours. We found that EGFR inhibition mediated a higher infiltration of immune cells and increased local proliferation of T-cells in the tumours. Moreover, inhibiting EGFR signalling led to increased activation of immune cells in the TME. Most strikingly, combined simultaneous blockade of EGFR and anti-PD-1 (aPD-1) enhanced tumour treatment response in a transgenic mouse model of EGFR-driven NSCLC. Thus, our findings show that EGFR inhibition promotes an active and proinflammatory immune cell infiltrate in the TME while improving response to immune checkpoint inhibitors in EGFR-driven NSCLC.

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EGFR: The Paradigm of an Oncogene-Driven Lung Cancer.

Publications

EGFR: The Paradigm of an Oncogene-Driven Lung Cancer.

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