Jessica A Hellyer1, Henning Stehr2, Millie Das3, Sukhmani K Padda1, Kavitha Ramchandran1, Joel W Neal1, Maximilian Diehn4, Heather A Wakelee5. 1. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, 94305, USA. 2. Department of Pathology, Stanford University School of Medicine, Stanford, CA, 94305, USA. 3. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, 94305, USA; Department of Medicine, VA Palo Alto Health Care System, Palo Alto, CA, USA. 4. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA; Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, 94305, USA. Electronic address: diehn@stanford.edu. 5. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, 94305, USA. Electronic address: hwakelee@stanford.edu.
Abstract
OBJECTIVES: For patients with Epidermal Growth Factor Receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), frontline EGFR-tyrosine kinase inhibitor (TKI) therapy compared to chemotherapy improves outcomes. However, resistance to these agents uniformly develops. Recently, mutations in the KEAP1-NFE2L2 pathway have been implicated as a potential mechanism of acquired EGFR TKI resistance. MATERIALS AND METHODS: We examined all patients with metastatic NSCLC with mutations in both EGFR and KEAP1/NFE2L2/CUL3 identified on next generation sequencing from 2015 - 2018. These patients were compared to a NSCLC control cohort with mutations in EGFR and wild type in KEAP1/NFE2L2/CUL3 matched on the basis of sex, smoking status, age and race. Time to treatment failure on EGFR TKI therapy and overall survival were examined. RESULTS: Among 228 EGFR mutant NSCLCs, 17 (7%) also carried mutations in KEAP1, NFE2L2, or CUL3. The most common co-mutation in both the KEAP1/NFE2L2/CUL3 mutant and wild-type cohort was TP53. Patients with KEAP1/NFE2L2/CUL3 mutations had a shorter median time to treatment failure on EGFR TKI (4.7 months) compared with the wild-type matched cohort (13.0 months), p= 0.0014. There was no difference in overall survival. CONCLUSION: For NSCLC patients with mutations in EGFR, co-mutations in KEAP1/NFE2L2/CUL3 are associated with significantly decreased time to treatment failure. Our results suggest that these mutations represent a mechanism of intrinsic resistance to TKI treatment.
OBJECTIVES: For patients with Epidermal Growth Factor Receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), frontline EGFR-tyrosine kinase inhibitor (TKI) therapy compared to chemotherapy improves outcomes. However, resistance to these agents uniformly develops. Recently, mutations in the KEAP1-NFE2L2 pathway have been implicated as a potential mechanism of acquired EGFR TKI resistance. MATERIALS AND METHODS: We examined all patients with metastatic NSCLC with mutations in both EGFR and KEAP1/NFE2L2/CUL3 identified on next generation sequencing from 2015 - 2018. These patients were compared to a NSCLC control cohort with mutations in EGFR and wild type in KEAP1/NFE2L2/CUL3 matched on the basis of sex, smoking status, age and race. Time to treatment failure on EGFR TKI therapy and overall survival were examined. RESULTS: Among 228 EGFR mutant NSCLCs, 17 (7%) also carried mutations in KEAP1, NFE2L2, or CUL3. The most common co-mutation in both the KEAP1/NFE2L2/CUL3 mutant and wild-type cohort was TP53. Patients with KEAP1/NFE2L2/CUL3 mutations had a shorter median time to treatment failure on EGFR TKI (4.7 months) compared with the wild-type matched cohort (13.0 months), p= 0.0014. There was no difference in overall survival. CONCLUSION: For NSCLCpatients with mutations in EGFR, co-mutations in KEAP1/NFE2L2/CUL3 are associated with significantly decreased time to treatment failure. Our results suggest that these mutations represent a mechanism of intrinsic resistance to TKI treatment.
Authors: Giorgia Foggetti; Chuan Li; Hongchen Cai; Jessica A Hellyer; Wen-Yang Lin; Deborah Ayeni; Katherine Hastings; Jungmin Choi; Anna Wurtz; Laura Andrejka; Dylan G Maghini; Nicholas Rashleigh; Stellar Levy; Robert Homer; Scott N Gettinger; Maximilian Diehn; Heather A Wakelee; Dmitri A Petrov; Monte M Winslow; Katerina Politi Journal: Cancer Discov Date: 2021-03-11 Impact factor: 39.397
Authors: Kristen S Hill; Anthony McDowell; J Robert McCorkle; Erin Schuler; Sally R Ellingson; Rina Plattner; Jill M Kolesar Journal: Cancers (Basel) Date: 2021-04-14 Impact factor: 6.639