Reference Detail

Ref Type

Journal Article

PMID

(25714871)

Authors

Hechtman JF, Sadowska J, Huse JT, Borsu L, Yaeger R, Shia J, Vakiani E, Ladanyi M, Arcila ME

Title

AKT1 E17K in Colorectal Carcinoma Is Associated with BRAF V600E but Not MSI-H Status: A Clinicopathologic Comparison to PIK3CA Helical and Kinase Domain Mutants.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer research : MCR	13	6	2015 Jun	1003-8	Mol Cancer Res

URL

Abstract Text

The PI3K/AKT/mTOR pathway is activated through multiple mechanisms in colorectal carcinoma. Here, the clinicopathologic and molecular features of AKT1 E17K-mutated colorectal carcinoma in comparison with PIK3CA-mutated colorectal carcinoma are described in detail. Interestingly, in comparison with PIK3CA mutants, AKT1 E17K was significantly associated with mucinous morphology and concurrent BRAF V600E mutation. Among PIK3CA mutants, exon 21 mutations were significantly associated with BRAF V600E mutation, MSI-H status, and poor differentiation, while exon 10 mutations were associated with KRAS/NRAS mutations. Three of four AKT1 mutants with data from both primary and metastatic lesions had concordant AKT1 mutation status in both. Both AKT1- and PIK3CA-mutant colorectal carcinoma demonstrated frequent loss of PTEN expression (38% and 34%, respectively) and similar rates of p-PRAS 40 expression (63% and 50%, respectively). Both patients with AKT1 E17K alone had primary resistance to cetuximab, whereas 7 of 8 patients with PIK3CA mutation alone experienced tumor shrinkage or stability with anti-EGFR therapy. These results demonstrate that AKT1 E17K mutation in advanced colorectal carcinoma is associated with mucinous morphology, PIK3CA wild-type status, and concurrent RAS/RAF mutations with similar pattern to PIK3CA exon 21 mutants. Thus, AKT1 E17K mutations contribute to primary resistance to cetuximab and serve as an actionable alteration.This first systematic study of AKT1 and PIK3CA hotspot mutations and their association with cetuximab resistance and BRAF V600E mutation has important ramifications for the development of personalized medicine, particularly in identifying patient candidates for PI3K or AKT inhibitors.

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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

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PIK3CA E545K	colorectal cancer	sensitive	Cetuximab + Irinotecan	Case Reports/Case Series	Actionable	In a retrospective analysis, treatment with the combination of Erbitux (cetuximab) and Camptosar (irinotecan) resulted in stable disease in 50% (1/2) and 14 months without evidence of disease in 50% (1/2) of colorectal carcinoma patients harboring a PIK3CA E545K mutation (PMID: 25714871).	25714871
PIK3CA R88Q	colorectal cancer	predicted - sensitive	Cetuximab + Floxuridine + Fluorouracil + Irinotecan	Case Reports/Case Series	Actionable	In a retrospective analysis, treatment with the combination of Erbitux (cetuximab), Adrucil (fluorouracil), Camptosar (irinotecan), and Floxuridine resulted in at least 24 months without evidence of disease in a colorectal carcinoma patient harboring a PIK3CA R88Q mutation (PMID: 25714871).	25714871
PIK3CA E542K	colorectal cancer	predicted - sensitive	Cetuximab + Irinotecan	Case Reports/Case Series	Actionable	In a retrospective analysis, treatment with the combination of Erbitux (cetuximab) and Camptosar (irinotecan) resulted in a partial response in 50% (1/2) and stable disease in 50% (1/2) of colorectal carcinoma patients harboring a PIK3CA E542K mutation (PMID: 25714871).	25714871
PIK3CA H1047R	colorectal cancer	sensitive	Cetuximab	Case Reports/Case Series	Actionable	In a retrospective analysis, Erbitux (cetuximab) combined with radiation therapy resulted in stable disease for 6 months in a colorectal carcinoma patient harboring a PIK3CA H1047R mutation (PMID: 25714871).	25714871
PIK3CA E542V	colorectal cancer	predicted - sensitive	Cetuximab	Case Reports/Case Series	Actionable	In a retrospective analysis, Erbitux (cetuximab) treatment resulted in stable disease in a colorectal carcinoma patient harboring a PIK3CA E542V mutation (PMID: 25714871).	25714871