Reference Detail

Ref Type Journal Article
PMID (26644315)
Authors Russo M, Siravegna G, Blaszkowsky LS, Corti G, Crisafulli G, Ahronian LG, Mussolin B, Kwak EL, Buscarino M, Lazzari L, Valtorta E, Truini M, Jessop NA, Robinson HE, Hong TS, Mino-Kenudson M, Di Nicolantonio F, Thabet A, Sartore-Bianchi A, Siena S, Iafrate AJ, Bardelli A, Corcoran RB
Title Tumor Heterogeneity and Lesion-Specific Response to Targeted Therapy in Colorectal Cancer.
Journal Cancer discovery
Vol 6
Issue 2
Date 2016 Feb
URL
Abstract Text How genomic heterogeneity associated with acquired resistance to targeted agents affects response to subsequent therapy is unknown. We studied EGFR blockade in colorectal cancer to assess whether tissue and liquid biopsies can be integrated with radiologic imaging to monitor the impact of individual oncogenic alterations on lesion-specific responses. Biopsy of a patient's progressing liver metastasis following prolonged response to cetuximab revealed a MEK1(K57T) mutation as a novel mechanism of acquired resistance. This lesion regressed upon treatment with panitumumab and the MEK inhibitor trametinib. In circulating tumor DNA (ctDNA), mutant MEK1 levels declined with treatment, but a previously unrecognized KRAS(Q61H) mutation was also identified that increased despite therapy. This same KRAS mutation was later found in a separate nonresponding metastasis. In summary, parallel analyses of tumor biopsies and serial ctDNA monitoring show that lesion-specific radiographic responses to subsequent targeted therapies can be driven by distinct resistance mechanisms arising within separate tumor lesions in the same patient.Molecular heterogeneity ensuing from acquired resistance drives lesion-specific responses to subsequent targeted therapies. Analysis of a single-lesion biopsy is inadequate to guide selection of subsequent targeted therapies. ctDNA profiles allow the detection of concomitant resistance mechanisms residing in separate metastases and assessment of the effect of therapies designed to overcome resistance.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
K57T missense gain of function - predicted MAP2K1 K57T lies within the negative regulatory region of the Map2k1 protein (PMID: 24241536). K57T results in increased Erk1/2 phosphorylation in culture (PMID: 30341394), and has been demonstrated to occur as a secondary drug resistance mutation (PMID: 26644315, PMID: 28819429, PMID: 30341394), and therefore, is predicted to result in a gain of Map2k1 protein function. Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
MAP2K1 K57N colorectal cancer resistant Panitumumab Preclinical Actionable In a preclinical study, colorectal cancer cell lines expressing MAP2K1 K57N were insensitive to Vectibix (panitumumab) in culture (PMID: 26644315). 26644315
MAP2K1 K57T colorectal cancer sensitive Panitumumab + Trametinib Case Reports/Case Series Actionable In a clinical case study, a combination of Vectibix (panitumumab) and Mekinist (trametinib) caused tumor regression in a patient’s colorectal cancer metastases harboring MAP2K1 K57T after being identified pre-clinically as a combination likely to inhibit MAP2K1 K57T expressing colorectal cancer (PMID: 26644315). 26644315
MAP2K1 K57T colorectal cancer resistant Panitumumab Preclinical Actionable In a preclinical study, a colorectal cancer cell line expressing MAP2K1 K57T was resistant to Vectibix (panitumumab) in culture (PMID: 26644315). 26644315
MAP2K1 K57T colorectal cancer sensitive Cetuximab + Trametinib Preclinical Actionable In a preclinical study, Erbitux (cetuximab) and Mekinist (trametinib) inhibited colorectal cancer cell lines expressing MAP2K1 K57T in culture (PMID: 26644315). 26644315
MAP2K1 K57T colorectal cancer predicted - resistant Cetuximab Case Reports/Case Series Actionable In a clinical case study, a patient with colorectal cancer developed liver metastases harboring MAP2K1 K57T that were insensitive to Erbitux (cetuximab) treatment and the mutation was confirmed to cause resistance in human colorectal cancer cell lines in culture (PMID: 26644315). 26644315
MAP2K1 K57N colorectal cancer resistant Cetuximab Preclinical Actionable In a preclinical study, colorectal cancer cell lines expressing MAP2K1 K57N were insensitive to Erbitux (cetuximab) in culture (PMID: 26644315). 26644315
MAP2K1 K57N colorectal cancer sensitive Panitumumab + Trametinib Preclinical Actionable In a preclinical study, Vectibix (panitumumab) and Mekinist (trametinib) inhibited colorectal cancer cell lines expressing MAP2K1 K57N in culture (PMID: 26644315). 26644315
MAP2K1 K57N colorectal cancer sensitive Cetuximab + Trametinib Preclinical Actionable In a preclinical study, Erbitux (cetuximab) and Mekinist (trametinib) inhibited colorectal cancer cell lines expressing MAP2K1 K57N in culture (PMID: 26644315). 26644315
KRAS Q61H colorectal cancer predicted - resistant Panitumumab + Trametinib Case Reports/Case Series Actionable In a clinical case study, Vectibix (panitumumab) and Mekinist (trametinib) combination treatment inhibited growth of liver metastasis harboring MAP2K1 K57T in a patient with colorectal cancer, but the disease progressed due to the outgrowth of a clone of metastatic tumor harboring KRAS Q61H (PMID: 26644315). 26644315