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Anti-EGFR-resistant clones decay exponentially after progression: implications for anti-EGFR re-challenge.

ABSTRACT: BACKGROUND:Colorectal cancer (CRC) has been shown to acquire RAS and EGFR ectodomain mutations as mechanisms of resistance to epidermal growth factor receptor (EGFR) inhibition (anti-EGFR). After anti-EGFR withdrawal, RAS and EGFR mutant clones lack a growth advantage relative to other clones and decay; however, the kinetics of decay remain unclear. We sought to determine the kinetics of acquired RAS/EGFR mutations after discontinuation of anti-EGFR therapy. PATIENTS AND METHODS:We present the post-progression circulating tumor DNA (ctDNA) profiles of 135 patients with RAS/BRAF wild-type metastatic CRC treated with anti-EGFR who acquired RAS and/or EGFR mutations during therapy. Our validation cohort consisted of an external dataset of 73 patients with a ctDNA profile suggestive of prior anti-EGFR exposure and serial sampling. A separate retrospective cohort of 80 patients was used to evaluate overall response rate and progression free survival during re-challenge therapies. RESULTS:Our analysis showed that RAS and EGFR relative mutant allele frequency decays exponentially (r2=0.93 for RAS; r2=0.94 for EGFR) with a cumulative half-life of 4.4?months. We validated our findings using an external dataset of 73 patients with a ctDNA profile suggestive of prior anti-EGFR exposure and serial sampling, confirming exponential decay with an estimated half-life of 4.3?months. A separate retrospective cohort of 80 patients showed that patients had a higher overall response rate during re-challenge therapies after increasing time intervals, as predicted by our model. CONCLUSION:These results provide scientific support for anti-EGFR re-challenge and guide the optimal timing of re-challenge initiation.

SUBMITTER: Parseghian CM

PROVIDER: S-EPMC6657008 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Anti-EGFR-resistant clones decay exponentially after progression: implications for anti-EGFR re-challenge.

Parseghian C M CM Loree J M JM Morris V K VK Liu X X Clifton K K KK Napolitano S S Henry J T JT Pereira A A AA Vilar E E Johnson B B Kee B B Raghav K K Dasari A A Wu J J Garg N N Raymond V M VM Banks K C KC Talasaz A A AA Lanman R B RB Strickler J H JH Hong D S DS Corcoran R B RB Overman M J MJ Kopetz S S

Annals of oncology : official journal of the European Society for Medical Oncology 20190201 2

<h4>Background</h4>Colorectal cancer (CRC) has been shown to acquire RAS and EGFR ectodomain mutations as mechanisms of resistance to epidermal growth factor receptor (EGFR) inhibition (anti-EGFR). After anti-EGFR withdrawal, RAS and EGFR mutant clones lack a growth advantage relative to other clones and decay; however, the kinetics of decay remain unclear. We sought to determine the kinetics of acquired RAS/EGFR mutations after discontinuation of anti-EGFR therapy.<h4>Patients and methods</h4>W ...[more]

PMID: 30462160

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Project description:BackgroundGenetic and metabolic heterogeneity are well-known features of cancer and tumors can be viewed as an evolving mix of subclonal populations, subjected to selection driven by microenvironmental pressures or drug treatment. In previous studies, anti-VEGF therapy was found to elicit rewiring of tumor metabolism, causing marked alterations in glucose, lactate ad ATP levels in tumors. The aim of this study was to evaluate whether differences in the sensitivity to glucose starvation existed at the clonal level in ovarian cancer cells and to investigate the effects induced by anti-VEGF therapy on this phenotype by multi-omics analysis.MethodsClonal populations, obtained from both ovarian cancer cell lines (IGROV-1 and SKOV3) and tumor xenografts upon glucose deprivation, were defined as glucose deprivation resistant (GDR) or glucose deprivation sensitive (GDS) clones based on their in vitro behaviour. GDR and GDS clones were characterized using a multi-omics approach, including genetic, transcriptomic and metabolic analysis, and tested for their tumorigenic potential and reaction to anti-angiogenic therapy.ResultsTwo clonal populations, GDR and GDS, with strikingly different viability following in vitro glucose starvation, were identified in ovarian cancer cell lines. GDR clones survived and overcame glucose starvation-induced stress by enhancing mitochondrial oxidative phosphorylation (OXPHOS) and both pyruvate and lipids uptake, whereas GDS clones were less able to adapt and died. Treatment of ovarian cancer xenografts with the anti-VEGF drug bevacizumab positively selected for GDR clones that disclosed increased tumorigenic properties in NOD/SCID mice. Remarkably, GDR clones were more sensitive than GDS clones to the mitochondrial respiratory chain complex I inhibitor metformin, thus suggesting a potential therapeutic strategy to target the OXPHOS-metabolic dependency of this subpopulation.ConclusionA glucose-deprivation resistant population of ovarian cancer cells showing druggable OXPHOS-dependent metabolic traits is enriched in experimental tumors treated by anti-VEGF therapy.

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Anti-EGFR-resistant clones decay exponentially after progression: implications for anti-EGFR re-challenge.

Publications

Anti-EGFR-resistant clones decay exponentially after progression: implications for anti-EGFR re-challenge.

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