title: Acquired Resistance to the Mutant-Selective EGFR Inhibitor AZD9291 Is Associated with Increased Dependence on RAS Signaling in Preclinical Models.
abstract: Resistance to targeted EGFR inhibitors is likely to develop in EGFR-mutant lung cancers. Early identification of innate or acquired resistance mechanisms to these agents is essential to direct development of future therapies. We describe the detection of heterogeneous mechanisms of resistance within populations of EGFR-mutant cells (PC9 and/or NCI-H1975) with acquired resistance to current and newly developed EGFR tyrosine kinase inhibitors, including AZD9291. We report the detection of NRAS mutations, including a novel E63K mutation, and a gain of copy number of WT NRAS or WT KRAS in cell populations resistant to gefitinib, afatinib, WZ4002, or AZD9291. Compared with parental cells, a number of resistant cell populations were more sensitive to inhibition by the MEK inhibitor selumetinib (AZD6244; ARRY-142886) when treated in combination with the originating EGFR inhibitor. In vitro, a combination of AZD9291 with selumetinib prevented emergence of resistance in PC9 cells and delayed resistance in NCI-H1975 cells. In vivo, concomitant dosing of AZD9291 with selumetinib caused regression of AZD9291-resistant tumors in an EGFRm/T790M transgenic model. Our data support the use of a combination of AZD9291 with a MEK inhibitor to delay or prevent resistance to AZD9291 in EGFRm and/or EGFRm/T790M tumors. Furthermore, these findings suggest that NRAS modifications in tumor samples from patients who have progressed on current or EGFR inhibitors in development may support subsequent treatment with a combination of EGFR and MEK inhibition.
authors: AstraZeneca Oncology Innovative Medicines, Alderley Park, Macclesfield, Cheshire, United Kingdom.
authors: Catherine A
authors: CA
authors: Eberlein
authors: AstraZeneca Oncology Innovative Medicines, Gatehouse Park, Waltham, Massachusetts.
authors: Daniel
authors: D
authors: Stetson
authors: AstraZeneca Oncology Innovative Medicines, Gatehouse Park, Waltham, Massachusetts.
authors: Aleksandra A
authors: AA
authors: Markovets
authors: AstraZeneca Oncology Innovative Medicines, Alderley Park, Macclesfield, Cheshire, United Kingdom.
authors: Katherine J
authors: KJ
authors: Al-Kadhimi
authors: AstraZeneca Oncology Innovative Medicines, Gatehouse Park, Waltham, Massachusetts.
authors: Zhongwu
authors: Z
authors: Lai
authors: AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom.
authors: Paul R
authors: PR
authors: Fisher
authors: Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee.
authors: Catherine B
authors: CB
authors: Meador
authors: Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee.
authors: Paula
authors: P
authors: Spitzler
authors: Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee.
authors: Eiki
authors: E
authors: Ichihara
authors: AstraZeneca Oncology Innovative Medicines, Alderley Park, Macclesfield, Cheshire, United Kingdom.
authors: Sarah J
authors: SJ
authors: Ross
authors: AstraZeneca Oncology Innovative Medicines, Alderley Park, Macclesfield, Cheshire, United Kingdom.
authors: Miika J
authors: MJ
authors: Ahdesmaki
authors: AstraZeneca Oncology Innovative Medicines, Gatehouse Park, Waltham, Massachusetts.
authors: Ambar
authors: A
authors: Ahmed
authors: AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom.
authors: Laura E
authors: LE
authors: Ratcliffe
authors: AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom.
authors: Elizabeth L Christey
authors: EL
authors: O'Brien
authors: AstraZeneca Oncology Innovative Medicines, Alderley Park, Macclesfield, Cheshire, United Kingdom.
authors: Claire H
authors: CH
authors: Barnes
authors: AstraZeneca Oncology Innovative Medicines, Alderley Park, Macclesfield, Cheshire, United Kingdom.
authors: Henry
authors: H
authors: Brown
authors: AstraZeneca Oncology Innovative Medicines, Alderley Park, Macclesfield, Cheshire, United Kingdom.
authors: Paul D
authors: PD
authors: Smith
authors: AstraZeneca Oncology Innovative Medicines, Gatehouse Park, Waltham, Massachusetts.
authors: Jonathan R
authors: JR
authors: Dry
authors: AstraZeneca Oncology Innovative Medicines, Alderley Park, Macclesfield, Cheshire, United Kingdom.
authors: Garry
authors: G
authors: Beran
authors: AstraZeneca Oncology Innovative Medicines, Gatehouse Park, Waltham, Massachusetts.
authors: Kenneth S
authors: KS
authors: Thress
authors: AstraZeneca Oncology Innovative Medicines, Gatehouse Park, Waltham, Massachusetts.
authors: Brian
authors: B
authors: Dougherty
authors: Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee.
authors: William
authors: W
authors: Pao
authors: AstraZeneca Oncology Innovative Medicines, Alderley Park, Macclesfield, Cheshire, United Kingdom. Darren.Cross@astrazeneca.com.
authors: Darren A E
authors: DA
authors: Cross
mesh_terms: D000178:Acrylamides / Q000008:administration & dosage / Q000494:pharmacology*; D000814:Aniline Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001562:Benzimidazoles / Q000008:administration & dosage; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D009154:Mutation; D015398:Signal Transduction; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism; D007211:Indoles; D011743:Pyrimidines
chemical_list: D000178:Acrylamides; D000814:Aniline Compounds; D001562:Benzimidazoles; D066246:ErbB Receptors; D018631:ras Proteins; C517975:AZD 6244; C000596361:osimertinib; D007211:Indoles; D011743:Pyrimidines