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	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	6	2	2016 Feb	147-153	Cancer Discov

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	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
MAP2K1	K57T	missense	gain of function	MAP2K1 K57T lies within the negative regulatory region of the Map2k1 protein (PMID: 24241536). K57T confers a gain of function to Map2k1 as demonstrated by increased Erk1/2 phosphorylation (PMID: 30341394, PMID: 32641410) and transformation activity in cultured cells and increased proliferation in a competition assay (PMID: 36442478), and occurs as a secondary drug resistance mutation in the context of BRAF inhibitors (PMID: 26644315, PMID: 28819429, PMID: 30341394).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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 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 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	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
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 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	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