Dataset Information

KRAS mutation in colon cancer: a marker of resistance to EGFR-I therapy.

ABSTRACT:

Introduction and design

The introduction of the epidermal growth factor receptor inhibitors (EGFR-I) has increased the treatment options available for patients with metastatic colorectal cancer (mCRC). Two EGFR-I agents currently approved for the treatment of mCRC are the fully human monoclonal antibody panitumumab and the mouse-human chimeric monoclonal antibody cetuximab. While these agents have demonstrated activity across multiple lines of therapy, early studies suggested that clinical benefit was confined to a subset of patients treated. Mutation of the KRAS oncogene has emerged as a powerful negative predictive biomarker to identify patients with mCRC who do not benefit from EGFR-I therapy. Multiple retrospective analyses have demonstrated that clinical benefit from treatment with EGFR-I is limited to patients with tumors harboring the wild-type KRAS gene. In this review, the KRAS pathway and studies evaluating KRAS as a prognostic marker in CRC are discussed along with advances in KRAS gene mutation testing. Clinical trials evaluating the role of KRAS status in response to EGFR-I monotherapy or in combination with chemotherapy are also highlighted along with ongoing studies evaluating the role of EGFR-I treatment on curative resections rates.

Results and conclusion

Future studies investigating EGFR-I therapy in mCRC should incorporate KRAS mutation testing into the study protocol in order to more accurately determine the patient population that will obtain clinical benefit from these novel agents.

SUBMITTER: Siddiqui AD

PROVIDER: S-EPMC2840670 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Publications

KRAS mutation in colon cancer: a marker of resistance to EGFR-I therapy.

Siddiqui Ahmad D AD Piperdi Bilal B

Annals of surgical oncology 20091120 4

<h4>Introduction and design</h4>The introduction of the epidermal growth factor receptor inhibitors (EGFR-I) has increased the treatment options available for patients with metastatic colorectal cancer (mCRC). Two EGFR-I agents currently approved for the treatment of mCRC are the fully human monoclonal antibody panitumumab and the mouse-human chimeric monoclonal antibody cetuximab. While these agents have demonstrated activity across multiple lines of therapy, early studies suggested that clinic ...[more]

PMID: 19936839

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Project description:BackgroundColorectal cancer (CRC) is associated with resistance to anti-epidermal growth factor receptor (EGFR) antibodies (both acquired and intrinsic), owing to the amplification or mutation of the KRAS oncogene. However, the mechanism underlying this resistance is incompletely understood.MethodsDLD1 cells with WT (+/-) or KRAS G13D mutant allele were treated with different concentrations of Cetuximab (Cet) or panitumumab (Pab) to study the mechanism underlying the KRAS mutation-induced resistance to anti-EGFR antibodies. The function of AMPK in KRAS mutation-induced resistance to anti-EGFR antibodies in CRC cells, and the regulatory role of Bcl-2 family proteins in DLD1 cells with WT or mutated KRAS upon AMPK activation were investigated. In addition, xenograft tumor models with the nude mouse using DLD1 cells with WT or mutated KRAS were established to examine the effects of AMPK activation on KRAS mutation-mediated anti-EGFR antibody resistance.ResultsHigher levels of AMPK activity in CRC cells with wild-type KRAS treated with anti-EGFR antibody resulted in apoptosis induction. In contrast, CRC cells with mutated KRAS showed lower AMP-activated protein kinase (AMPK) activity and decreased sensitivity to the inhibitory effect of anti-EGFR antibody. CRC cells with mutated KRAS showed high levels of glycolysis and produced an excessive amount of ATP, which suppressed AMPK activation. The knockdown of AMPK expression in CRC cells with WT KRAS produced similar effects to those observed in cells with mutated KRAS and decreased their sensitivity to cetuximab. On the contrary, the activation of AMPK by metformin (Met) or 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) could overcome the KRAS-induced resistance to the anti-EGFR antibody in vivo and in vitro. The activation of AMPK resulted in the inhibition of myeloid cell leukemia 1 (Mcl-1) translation through the suppression of the mammalian target of rapamycin (mTOR) pathway.ConclusionThe results established herein indicate that targeting AMPK is a potentially promising and effective CRC treatment strategy. Video abstract.

Project description:Mutations in RAS occur in 30-50% of metastatic colorectal carcinomas (mCRCs) and correlate with resistance to anti-EGFR therapy. Consequently, mCRC biomarker guidelines state RAS mutational testing should be performed when considering EGFR inhibitor treatment. However, a small subset of mCRCs are reported to harbor RAS amplification. In order to elucidate the clinicopathologic features and anti-EGFR treatment response associated with RAS amplification, we retrospectively reviewed a large cohort of mCRC patients that underwent targeted next-generation sequencing and copy number analysis for KRAS, NRAS, HRAS, BRAF, and PIK3CA. Molecular testing was performed on 1286 consecutive mCRC from 1271 patients as part of routine clinical care, and results were correlated with clinicopathologic findings, mismatch repair (MMR) status and follow-up. RAS amplification was detected in 22 (2%) mCRCs and included: KRAS, NRAS, and HRAS for 15, 5, and 2 cases, respectively (6-21 gene copies). Patients with a KRAS-amplified mCRC were more likely to report a history of inflammatory bowel disease (p < 0.001). In contrast, mutations in KRAS were associated with older patient age, right-sided colonic origin, low-grade differentiation, mucinous histology, and MMR proficiency (p ≤ 0.017). Four patients with a KRAS-amplified mCRC and no concomitant RAS/BRAF/PIK3CA mutations received EGFR inhibitor-based therapy, and none demonstrated a clinicoradiographic response. The therapeutic impact of RAS amplification was further evaluated using a separate, multi-institutional cohort of 23 patients. Eight of 23 patients with KRAS-amplified mCRC received anti-EGFR therapy and all 8 patients exhibited disease progression on treatment. Although the number of KRAS-amplified mCRCs is limited, our data suggest the clinicopathologic features associated with mCRC harboring a KRAS amplification are distinct from those associated with a KRAS mutation. However, both alterations seem to confer EGFR inhibitor resistance and, therefore, RAS testing to include copy number analyses may be of consideration in the treatment of mCRC.

Dataset Information

KRAS mutation in colon cancer: a marker of resistance to EGFR-I therapy.

Introduction and design

Results and conclusion

Publications

KRAS mutation in colon cancer: a marker of resistance to EGFR-I therapy.

Similar Datasets

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