Dataset Information

Impact of Concurrent PIK3CA Mutations on Response to EGFR Tyrosine Kinase Inhibition in EGFR-Mutant Lung Cancers and on Prognosis in Oncogene-Driven Lung Adenocarcinomas.

ABSTRACT: INTRODUCTION:In patients with epidermal growth factor receptor (EGFR)-mutant or KRAS-mutant lung adenocarcinomas, the prognostic impact of a concurrent PIK3CA mutation remains unclear. Although preclinical data suggest that sensitivity to EGFR tyrosine kinase inhibition (TKI) is decreased in EGFR-mutant lung cancers also harboring a PIK3CA mutation, this interaction has not been explored clinically. METHODS:Patients with lung adenocarcinomas harboring a PIK3CA mutation concurrent with a separate driver mutation were identified through mutational hotspot testing, multiplex sizing assays, and fluorescence in situ hybridization. Overall survival and outcomes with EGFR TKI monotherapy (EGFR-mutant) were estimated using Kaplan-Meier methods and compared between double-mutant (EGFR-mutant or KRAS-mutant, concurrent PIK3CA-mutant) and single-mutant patients (EGFR-mutant or KRAS-mutant, PIK3CA wild-type) using log-rank tests. RESULTS:In EGFR-mutant and KRAS-mutant lung cancers, a concurrent PIK3CA mutation was associated with a decrease in median overall survival: 18 versus 33 months (EGFR double mutant, n = 10 versus single mutant, n = 43, p = 0.006), and 9 versus 16 months (KRAS double mutant, n = 16 versus single mutant, n = 47, p = 0.020). In EGFR-mutant lung cancers, a concurrent PIK3CA mutation did not impact benefit from EGFR TKI monotherapy. Single versus double mutant: objective response rate, 83% (n = 29) versus 62% (n = 6, p = 0.80); median time to progression, 11 (n = 29) versus 8 months (n = 6, p = 0.84); and median duration of TKI therapy, 15 (n = 32) versus 15 months (n = 10, p = 0.65). CONCLUSION:A concurrent PIK3CA mutation is a poor prognostic factor in patients with advanced EGFR-mutant or KRAS-mutant lung adenocarcinomas. There was no evidence that clinical benefit from EGFR TKI monotherapy is affected by a concurrent PIK3CA mutation in EGFR-mutant lung cancers.

SUBMITTER: Eng J

PROVIDER: S-EPMC4760768 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Impact of Concurrent PIK3CA Mutations on Response to EGFR Tyrosine Kinase Inhibition in EGFR-Mutant Lung Cancers and on Prognosis in Oncogene-Driven Lung Adenocarcinomas.

Eng Juliana J Woo Kaitlin M KM Sima Camelia S CS Plodkowski Andrew A Hellmann Matthew D MD Chaft Jamie E JE Kris Mark G MG Arcila Maria E ME Ladanyi Marc M Drilon Alexander A

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 20151201 12

<h4>Introduction</h4>In patients with epidermal growth factor receptor (EGFR)-mutant or KRAS-mutant lung adenocarcinomas, the prognostic impact of a concurrent PIK3CA mutation remains unclear. Although preclinical data suggest that sensitivity to EGFR tyrosine kinase inhibition (TKI) is decreased in EGFR-mutant lung cancers also harboring a PIK3CA mutation, this interaction has not been explored clinically.<h4>Methods</h4>Patients with lung adenocarcinomas harboring a PIK3CA mutation concurrent ...[more]

PMID: 26334752

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Project description:Epidermal growth factor receptor EGFR major driver mutations may affect downstream molecular networks and pathways, which would influence treatment outcomes of non-small cell lung cancer (NSCLC). This study aimed to unveil profiles of mutant proteins expressed in lung adenocarcinomas of 36 patients harboring representative driver EGFR mutations (Ex19del, nine; L858R, nine; no Ex19del/L858R, 18). Surprisingly, the orthogonal partial least squares discriminant analysis performed for identified mutant proteins demonstrated the profound differences in distance among the different EGFR mutation groups, suggesting that cancer cells harboring L858R or Ex19del emerge from cellular origins different from L858R/Ex19del-negative cells. Weighted gene coexpression network analysis, together with over-representative analysis, identified 18 coexpressed modules and their eigen proteins. Pathways enriched differentially for both the L858R and Ex19del mutations included carboxylic acid metabolic process, cell cycle, developmental biology, cellular responses to stress, mitotic prophase, cell proliferation, growth, epithelial to mesenchymal transition (EMT), and immune system. The IPA causal network analysis identified the highly activated networks of PARPBP, HOXA1, and APH1 under the L858R mutation, whereas those of ASGR1, APEX1, BUB1, and MAPK10 were highly activated under the Ex19del mutation. Interestingly, the downregulated causal network of osimertinib intervention showed the highest significance in overlap p-value among most causal networks predicted under the L858R mutation. We also identified the causal network of MAPK interacting serine/threonine kinase 1/2 (MNK1/2) highly activated differentially under the L858R mutation. Tumor-suppressor AMOT, a component of the Hippo pathways, was highly inhibited commonly under both L858R and Ex19del mutations. Our results could identify disease-related protein molecular networks from the landscape of single amino acid variants. Our findings may help identify potential therapeutic targets and develop therapeutic strategies to improve patient outcomes.

Project description:BackgroundMutations in the epidermal growth factor receptor (EGFR) gene are associated with increased sensitivity of lung cancers to kinase inhibitors like erlotinib. Mechanisms of cell death that occur after kinase inhibition in these oncogene-dependent tumors have not been well delineated. We sought to improve understanding of this process in order to provide insight into mechanisms of sensitivity and/or resistance to tyrosine kinase inhibitors and to uncover new targets for therapy.Methods and findingsUsing a panel of human lung cancer cell lines that harbor EGFR mutations and a variety of biochemical, molecular, and cellular techniques, we show that EGFR kinase inhibition in drug-sensitive cells provokes apoptosis via the intrinsic pathway of caspase activation. The process requires induction of the proapoptotic BH3-only BCL2 family member BIM (i.e., BCL2-like 11, or BCL2L11); erlotinib dramatically induces BIM levels in sensitive but not in resistant cell lines, and knockdown of BIM expression by RNA interference virtually eliminates drug-induced cell killing in vitro. BIM status is regulated at both transcriptional and posttranscriptional levels and is influenced by the extracellular signal-regulated kinase (ERK) signaling cascade downstream of EGFR. Consistent with these findings, lung tumors and xenografts from mice bearing mutant EGFR-dependent lung adenocarcinomas display increased concentrations of Bim after erlotinib treatment. Moreover, an inhibitor of antiapoptotic proteins, ABT-737, enhances erlotinib-induced cell death in vitro.ConclusionsIn drug-sensitive EGFR mutant lung cancer cells, induction of BIM is essential for apoptosis triggered by EGFR kinase inhibitors. This finding implies that the intrinsic pathway of caspase activation may influence sensitivity and/or resistance of EGFR mutant lung tumor cells to EGFR kinase inhibition. Manipulation of the intrinsic pathway could be a therapeutic strategy to enhance further the clinical outcomes of patients with EGFR mutant lung tumors.

Dataset Information

Impact of Concurrent PIK3CA Mutations on Response to EGFR Tyrosine Kinase Inhibition in EGFR-Mutant Lung Cancers and on Prognosis in Oncogene-Driven Lung Adenocarcinomas.

Publications

Impact of Concurrent PIK3CA Mutations on Response to EGFR Tyrosine Kinase Inhibition in EGFR-Mutant Lung Cancers and on Prognosis in Oncogene-Driven Lung Adenocarcinomas.

Similar Datasets

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