Addressing the elephant in the room, therapeutic resistance in non-small cell lung cancer, with epigenetic therapies

Corey A. Carter _, Karen Zeman, Regina M. Day, Patrick Richard, Arnold Oronsky, Neil Oronsky, Michelle Lybeck, Jan Scicinski and Bryan Oronsky

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Oncotarget. 2016; 7:40781-40791. https://doi.org/10.18632/oncotarget.8205

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Corey A. Carter1, Karen Zeman2, Regina M. Day3, Patrick Richard3, Arnold Oronsky4, Neil Oronsky5, Michelle Lybeck6, Jan Scicinski6 and Bryan Oronsky6

1 Walter Reed National Military Medical Center, Bethesda, MD, USA

2 National Naval Medical Center, Bethesda, MD, USA

3 Uniformed Services University of The Health Sciences, Bethesda, MD, USA

InterWest Partners, Menlo Park, CA, USA

5 CFLS Data, Mountain View, CA, USA

6 EpicentRx, Inc, Mountain View, CA, USA

Correspondence to:

Corey A. Carter, email:

Keywords: non small cell lung cancer; oncology; epigenetics; resistance

Received: December 12, 2015 Accepted: March 07, 2016 Published: March 19, 2016


Like Chinese boxes nesting inside each other, the classification of non-small cell lung cancer (NSCLC) is subdivided into smaller and smaller subtypes on the basis of histological and molecular attributes. The latter characterizes NSCLC by its molecular alterations and the identification of inhibitors that target these cancer-specific “driver” mutations. Despite the initial promise of precision-guided therapies to inhibit a finer and finer array of molecular subcategories, despite even the curative potential of immunotherapeutic checkpoint blockade, in particular, casualties still abound and true clinical success stories are few and far between; the ever-present, if sometimes unmentioned, “elephant in the room”, is the acquisition of resistance, which, sooner or later, rears its ugly head to undermine treatment success and shorten survival. Emerging data suggests that epigenetic therapies are able to reprogram the aberrant tumor-associated epigenome and ‘tame the beast of resistance’, thereby prolonging survival. This article reviews the role of epigenetic dysregulation in NSCLC, explores PFS2 as a possible surrogate endpoint, briefly mentions possible biomarkers and highlights combinatorial treatment epigenetic strategies to “prime” tumors and reverse resistance.

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