Acquired Resistance of EGFR-Mutant Lung Adenocarcinomas to Afatinib plus Cetuximab Is Associated with Activation of mTORC1

Pirazzoli, Valentina; Nebhan, Caroline A.; Song, Xiaoling; Wurtz, Anna; Walther, Zenta; Cai, Guoping; Zhao, Zhongming; Jia, Peilin; Stanchina, Elisa de; Shapiro, Erik M.; Gale, Molly; Yin, Ruonan; Horn, Leora; Carbone, David P.; Stephens, Philip J.; Miller, Vincent A.; Gettinger, Scott; Pao, William; Politi, Katerina

doi:10.1016/j.celrep.2014.04.014

Cited by 69 publications

(58 citation statements)

References 20 publications

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“…Direct effectors of RAS such as BRAF and MAP2K1 also strongly scored, as did additional MAPK pathways that may function in various feedback mechanisms at play in RTK signaling. Genes involved in the PI3K pathway that act downstream from RTKs, such as PIK3R1, PTEN, NF2 (Pirazzoli et al 2014), and AKT1, were also recovered in our screens. One interesting observation from the OG screen was that expression of most of the OGs that provided enrichment in the presence of gefitinib resulted in a negative enrichment score when expressed in cells bearing activated EGFR without gefitinib (Fig.…”

Section: Discussionmentioning

confidence: 92%

A genetic interaction analysis identifies cancer drivers that modify EGFR dependency

et al. 2017

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A large number of cancer drivers have been identified through tumor sequencing efforts, but how they interact and the degree to which they can substitute for each other have not been systematically explored. To comprehensively investigate how cancer drivers genetically interact, we searched for modifiers of epidermal growth factor receptor (EGFR) dependency by performing CRISPR, shRNA, and expression screens in a non-small cell lung cancer (NSCLC) model. We elucidated a broad spectrum of tumor suppressor genes (TSGs) and oncogenes (OGs) that can genetically modify proliferation and survival of cancer cells when EGFR signaling is altered. These include genes already known to mediate EGFR inhibitor resistance as well as many TSGs not previously connected to EGFR and whose biological functions in tumorigenesis are not well understood. We show that mutation of PBRM1, a subunit of the SWI/SNF complex, attenuates the effects of EGFR inhibition in part by sustaining AKT signaling. We also show that mutation of Capicua (CIC), a transcriptional repressor, suppresses the effects of EGFR inhibition by partially restoring the EGFR-promoted gene expression program, including the sustained expression of Ets transcription factors such as ETV1. Together, our data provide strong support for the hypothesis that many cancer drivers can substitute for each other in certain contexts and broaden our understanding of EGFR regulation.

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Section: Discussionmentioning

confidence: 92%

A genetic interaction analysis identifies cancer drivers that modify EGFR dependency

et al. 2017

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“…Activation of the mTOR pathway via mutation and loss of the inhibitory function of TSC2 is well known to be associated with acquired resistance to targeted therapy and could be linked to the de novo resistance observed in this patient [12]. The other nonresponding patient who was ALK FISH negative died within 1 week of receiving crizotinib, and was ultimately deemed "too sick to respond" by the treating physician.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Genomic Profiling Identifies a Subset of Crizotinib-Responsive ALK-Rearranged Non-Small Cell Lung Cancer Not Detected by Fluorescence In Situ Hybridization

Ali¹,

Hensing

Schrock³

et al. 2016

The Oncologist

111

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Introduction. For patients with non-small cell lung cancer (NSCLC) tobenefitfromALKinhibitors,sensitiveandspecificdetectionofALK genomic rearrangements is needed. ALK break-apart fluorescence in situ hybridization (FISH) is the U.S. Food and Drug Administration approved and standard-of-care diagnostic assay, but identification of ALK rearrangements by other methods reported in NSCLC cases that tested negative for ALK rearrangements by FISH suggests a significant false-negative rate. We report here a large series of NSCLC cases assayed by hybrid-capture-based comprehensive genomic profiling (CGP) in the course of clinical care. Materials and Methods. Hybrid-capture-based CGP using nextgenerationsequencingwasperformedinthe course ofclinicalcare of 1,070 patients with advanced lung cancer. Each tumor sample was evaluated for all classes of genomic alterations, including base-pair substitutions, insertions/deletions, copy number alterations and rearrangements, as well as fusions/rearrangements.

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“…Unfortunately, resistance to A+C has already been observed in patients. For example, activation of mTORC1 signaling may confer resistance to A+C in some tumors (22); however, a complete understanding of the spectrum of resistance mechanisms to A+C is currently lacking.…”

Section: Introductionmentioning

confidence: 99%

Optimizing the Sequence of Anti-EGFR–Targeted Therapy in EGFR-Mutant Lung Cancer

Meador

Jin

Stanchina

et al. 2015

Molecular Cancer Therapeutics

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Metastatic EGFR-mutant lung cancers are sensitive to the first- and second- generation EGFR tyrosine kinase inhibitors (TKIs), gefitinib, erlotinib, and afatinib, but resistance develops. Acquired resistance (AR) to gefitinib or erlotinib occurs most commonly (>50%) via the emergence of a second-site EGFR mutation, T790M. Two strategies to overcome T790M-mediated resistance are dual inhibition of EGFR with afatinib plus the anti-EGFR antibody, cetuximab (A+C), or mutant-specific EGFR inhibition with AZD9291. A+C and AZD9291 are now also being tested as first-line therapies, but whether these therapies will extend progression-free survival or induce more aggressive forms of resistance in this setting remains unknown. We modeled resistance to multiple generations of anti-EGFR therapies preclinically in order to understand the effects of sequential treatment with anti-EGFR agents on drug resistance and determine the optimal order of treatment. Using a panel of erlotinib/afatinib-resistant cells including a novel patient-derived cell line (VP-2), we found that AZD9291 was more potent than A+C at inhibiting cell growth and EGFR signaling in this setting. 4 of 4 xenograft-derived A+C-resistant cell lines displayed in vitro and in vivo sensitivity to AZD9291, but 4 of 4 AZD9291-resistant cell lines demonstrated cross-resistance to A+C. Addition of cetuximab to AZD9291 did not confer additive benefit in any preclinical disease setting. This work, emphasizing a mechanistic understanding of the effects of therapies on tumor evolution, provides a framework for future clinical trials testing different treatment sequences. This paradigm is applicable to other tumor types in which multiple generations of inhibitors are now available.

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Acquired Resistance of EGFR-Mutant Lung Adenocarcinomas to Afatinib plus Cetuximab Is Associated with Activation of mTORC1

Cited by 69 publications

References 20 publications

A genetic interaction analysis identifies cancer drivers that modify EGFR dependency

A genetic interaction analysis identifies cancer drivers that modify EGFR dependency

Comprehensive Genomic Profiling Identifies a Subset of Crizotinib-Responsive ALK-Rearranged Non-Small Cell Lung Cancer Not Detected by Fluorescence In Situ Hybridization

Optimizing the Sequence of Anti-EGFR–Targeted Therapy in EGFR-Mutant Lung Cancer

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