Molecular Heterogeneity and Receptor Coamplification Drive Resistance to Targeted Therapy in<i>MET</i>-Amplified Esophagogastric Cancer

Kwak, Eunice L.; Ahronian, Leanne G.; Siravegna, Giulia; Mussolin, Benedetta; Godfrey, Jason T.; Clark, Jeffrey W.; Blaszkowsky, Lawrence S.; Ryan, David P.; Lennerz, Jochen K.; Iafrate, A. John; Bardelli, Alberto; Hong, Theodore S.; Corcoran, Ryan B.

doi:10.1158/2159-8290.cd-15-0748

Cited by 165 publications

(144 citation statements)

References 28 publications

(45 reference statements)

Supporting

Mentioning

126

Contrasting

Unclassified

Order By: Relevance

“…Emerging clinical reports are consistent with our hypothesis that targeted therapies may fail in patients with GEA because the biomarker being tested to guide therapy is heterogeneously present within the patients' cancer. For instance, discordance in amplification of MET and other RTKs between the PT and metastatic sites has been shown to lead to failure of MET inhibition (35). In a recent FGFR inhibitor trial that was guided by FGFR2 amplification testing of the PT, many patients with FGFR2 + PTs failed to respond.…”

Section: Discussionmentioning

confidence: 99%

Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma

et al. 2018

View full text Add to dashboard Cite

Gastroesophageal adenocarcinoma (GEA) is a lethal disease where targeted therapies, even when guided by genomic biomarkers, have had limited effi cacy. A potential reason for the failure of such therapies is that genomic profi ling results could commonly differ between the primary and metastatic tumors. To evaluate genomic heterogeneity, we sequenced paired primary GEA and synchronous metastatic lesions across multiple cohorts, fi nding extensive differences in genomic alterations, including discrepancies in potentially clinically relevant alterations. Multiregion sequencing showed signifi cant discrepancy within the primary tumor (PT) and between the PT and disseminated disease, with oncogene amplifi cation profi les commonly discordant. In addition, a pilot analysis of cell-free DNA (cfDNA) sequencing demonstrated the feasibility of detecting genomic amplifi cations not detected in PT sampling. Lastly, we profi led paired primary tumors, metastatic tumors, and cfDNA from patients enrolled in the personalized antibodies for GEA (PANGEA) trial of targeted therapies in GEA and found that genomic biomarkers were recurrently discrepant between the PT and untreated metastases. Divergent primary and metastatic tissue profi ling led to treatment reassignment in 32% (9/28) of patients. In discordant primary and metastatic lesions, we found 87.5% concordance for targetable alterations in metastatic tissue and cfDNA, suggesting the potential for cfDNA profi ling to enhance selection of therapy. SIGNIFICANCE:We demonstrate frequent baseline heterogeneity in targetable genomic alterations in GEA, indicating that current tissue sampling practices for biomarker testing do not effectively guide precision medicine in this disease and that routine profi ling of metastatic lesions and/or cfDNA should be systematically evaluated. Cancer Discov; 8(1);[37][38][39][40][41][42][43][44][45][46][47][48]

show abstract

Section: Discussionmentioning

confidence: 99%

Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma

et al. 2018

View full text Add to dashboard Cite

show abstract

“…The ALK inhibitor crizotinib is well known to also bind to MET tyrosine kinase domain and has shown clinical activity in MET -amplifi ed cancers ( 24,25 ). Moreover, recent phase I data showed that crizotinib may be safely combined with vemurafenib without occurrence of signifi cant dose-limiting toxicities ( 17 ).…”

Section: Discussionmentioning

confidence: 99%

MET-Driven Resistance to Dual EGFR and BRAF Blockade May Be Overcome by Switching from EGFR to MET Inhibition inBRAF-Mutated Colorectal Cancer

et al. 2016

Self Cite

View full text Add to dashboard Cite

A patient with metastatic BRAF -mutated colorectal cancer initially responded to combined EGFR and BRAF inhibition with panitumumab plus vemurafenib. Preexisting cells with increased MET gene copy number in the archival tumor tissue likely underwent clonal expansion during treatment, leading to the emergence of MET amplifi cation in the rebiopsy taken at progression. In BRAF -mutated colorectal cancer cells, ectopic expression of MET conferred resistance to panitumumab and vemurafenib, which was overcome by combining BRAF and MET inhibition. Based on tumor genotyping and functional in vitro data, the patient was treated with the dual ALK-MET inhibitor crizotinib plus vemurafenib, thus switching to dual MET and BRAF blockade, with rapid and marked effectiveness of such strategy. Although acquired resistance is a major limitation to the clinical effi cacy of anticancer agents, the identifi cation of molecular targets emerging during the fi rst treatment may afford the opportunity to design the next line of targeted therapies, maximizing patient benefi t. SIGNIFICANCE:MET amplifi cation is here identifi ed-clinically and preclinically-as a new mechanism of resistance to EGFR and BRAF dual/triple block combinations in BRAF -mutated colorectal cancer. Switching from EGFR to MET inhibition, while maintaining BRAF inhibition, resulted in clinical benefi t after the occurrence of MET-driven acquired resistance. Cancer Discov; 6(9);

show abstract

“…3 MET amplification has been identified as a relevant molecular alteration in thoracic and upper abdominal cancers. 4–7 Indeed, multiple studies have demonstrated durable responses to MET inhibition among patients with MET -amplified cancers, including patients with CUP. 3,4–7 …”

Section: Discussionmentioning

confidence: 99%

Circulating Tumor DNA Identifies EGFR Coamplification as a Mechanism of Resistance to Crizotinib in a Patient with Advanced MET-Amplified Lung Adenocarcinoma

Dagogo‐Jack

Fabrizio²,

Lennerz

et al. 2017

Journal of Thoracic Oncology

View full text Add to dashboard Cite

Molecular Heterogeneity and Receptor Coamplification Drive Resistance to Targeted Therapy inMET-Amplified Esophagogastric Cancer

Cited by 165 publications

References 28 publications

Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma

Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma

MET-Driven Resistance to Dual EGFR and BRAF Blockade May Be Overcome by Switching from EGFR to MET Inhibition inBRAF-Mutated Colorectal Cancer

Circulating Tumor DNA Identifies EGFR Coamplification as a Mechanism of Resistance to Crizotinib in a Patient with Advanced MET-Amplified Lung Adenocarcinoma

Contact Info

Product

Resources

About