Hwang-Phill Kim

Seoul National University

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Tae‐You Kim

Seoul National University Hospital

Sae‐Won Han

Seoul National University Hospital

Gyeong Hoon Kang

Seoul National University Hospital

Sang-Hyun Song

Seoul National University

Yung‐Jue Bang

Seoul National University

Tae-You Kim

Seoul National University

Seock‐Ah Im

Seoul National University Hospital

Hyun-Soon Jong

Seoul National University

Sang Eun Lee

Seoul National University

Seung‐Yong Jeong

Seoul National University

Cooperative Institutions

Seoul National University

Seoul National University Hospital

New Generation University College

National University College

Yonsei University

Seoul National University Bundang Hospital

Korea University

Boramae Medical Center

Sungkyunkwan University

National Cancer Center

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RNA editing in RHOQ promotes invasion potential in colorectal cancer

The Journal of Experimental Medicine (2014)

Sae‐Won Han Hwang-Phill Kim Jong-Yeon Shin Eun-Goo Jeong Won‐Chul Lee

RNA editing can increase RNA sequence variation without altering the DNA sequence. By comparing whole-genome and transcriptome sequence data of a rectal cancer, we found novel tumor-associated increase of RNA editing in ras homologue family member Q (RHOQ) transcripts. The adenosine-to-inosine (A-to-I) editing results in substitution of asparagine with serine at residue 136. We observed a higher level of the RHOQ RNA editing in tumor compared with normal tissue in colorectal cancer (CRC). The degree of RNA editing was associated with RhoQ protein activity in CRC cancer cell lines. RhoQ N136S amino acid substitution increased RhoQ activity, actin cytoskeletal reorganization, and invasion potential. KRAS mutation further increased the invasion potential of RhoQ N136S in vitro. Among CRC patients, recurrence was more frequently observed in patients with tumors having edited RHOQ transcripts and mutations in the KRAS gene. In summary, we show that RNA editing is another mechanism of sequence alteration that contributes to CRC progression.

10.1084/jem.20132209

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Citations (108)

Circulating tumor DNA sequencing in colorectal cancer patients treated with first-line chemotherapy with anti-EGFR

Scientific Reports (2021)

Yoojoo Lim Sheehyun Kim Jun-Kyu Kang Hwang-Phill Kim Hoon Jang

Abstract Circulating tumor DNA (ctDNA) may reveal dynamic tumor status during therapy. We conducted serial ctDNA analysis to investigate potential association with clinical outcome in metastatic colorectal cancer (mCRC) patients receiving chemotherapy. Tissue KRAS / NRAS wild-type mCRC patients were enrolled and treated with first-line cetuximab-containing chemotherapy. ctDNA isolated from plasma were analyzed by next generation sequencing (NGS) with 16 targeted gene panel. Among 93 patients, 84 (90.3%) had at least 1 somatic mutation in baseline ctDNA samples (average 2.74). Five patients with KRAS or NRAS hotspot mutation in the ctDNA showed significantly worse progression-free survival (PFS) ( p = 0.029). Changes in average variant allele frequency (VAF) in ctDNA showed significant correlation with tumor size change at the time of first response evaluation ( p = 0.020) and progressive disease (PD) ( p = 0.042). Patients whose average VAF decreased below cutoff (< 1%) at the first evaluation showed significantly better PFS ( p < 0.001), and the average VAF change further discriminated the PFS in the patients in partial response ( p = 0.018). At the time of PD, 54 new mutations including KRAS and MAP2K1 emerged in ctDNA. ctDNA sequencing can provide mutation profile that could better reflect tumor mutation status and predict treatment outcome.

Circulating tumor DNA

10.1038/s41598-021-95345-4

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Evaluation of the Antitumor Effects and Mechanisms of PF00299804, a Pan-HER Inhibitor, Alone or in Combination with Chemotherapy or Targeted Agents in Gastric Cancer

Molecular Cancer Therapeutics (2011)

Hyun-Jin Nam Keith A. Ching Julie L.C. Kan Hwang-Phill Kim Sae‐Won Han

Abstract Recently, HER2-directed treatment, such as trastuzumab, has shown clinical benefit in HER2-amplified gastric cancer. On the basis of recent studies about epidermal growth factor receptor (EGFR) or HER2-targeting agents (including gefitinib, lapatinib, and trastuzumab) in gastric cancer, the potent effects of pan-HER inhibitors targeting the HER family are anticipated. In this study, we evaluated the activity and mechanisms of PF00299804, an irreversible pan-HER inhibitor, in gastric cancer in vitro and in vivo models. PF00299804 showed significant growth-inhibitory effects in HER2-amplified gastric cancer cells (SNU216, N87), and it had lower 50% inhibitory concentration values compared with other EGFR tyrosine kinase inhibitors, including gefitinib, lapatinib, BIBW-2992, and CI-1033. PF00299804 induced apoptosis and G1 arrest and inhibited phosphorylation of receptors in the HER family and downstream signaling pathways including STAT3, AKT, and extracellular signal–regulated kinases (ERK) in HER2-amplified gastric cancer cells. PF00299804 also blocked EGFR/HER2, HER2/HER3, and HER3/HER4 heterodimer formation as well as the association of HER3 with p85α in SNU216 cells. The combination of PF00299804 with clinically relevant chemotherapeutic agents or molecular-targeted agents including trastuzumab (an anti-HER2 monoclonal antibody), CP751871 (an IGF1R inhibitor), PD0325901 (an ERK1/2 inhibitor), and PF04691502 (a PI3K/mTOR inhibitor) produced synergistic effects. These findings indicate that PF00299804 can be used as a targeted therapy for the treatment of HER2-amplified gastric cancer through inhibition of HER family heterodimer formation and may augment antitumor efficacy of chemotherapeutic and/or molecular-targeted agents. Mol Cancer Ther; 11(2); 439–51. ©2011 AACR.

Lapatinib

EGFR Inhibitors

Targeted Therapy

Growth inhibition

10.1158/1535-7163.mct-11-0494

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Citations (72)

Antitumor activity of SK-7041, a novel histone deacetylase inhibitor, in human lung and breast cancer cells.

PubMed (2006)

Keun‐Wook Lee Jee Hyun Kim Jung‐Hyun Park Hwang-Phill Kim Sang-Hyun Song

A class of synthetic histone deacetylase (HDAC) inhibitors, which are hybrids of trichostatin A and MS-275 were previously developed. In this study, the antitumor effects of SK-7041, one of those novel HDAC inhibitors, was evaluated on lung and breast cancer cell lines.Human lung and breast cancer cells, as well as normal human bronchial epithelial (NHBE) cells were treated with SK-7041, and results were compared with those of cells treated with suberoylanilide hydroxamic acid (SAHA).SK-7041 induced time-dependent histone hyperacetylation and showed more potent cytotoxicity than SAHA in cancer cells. These antiproliferative effects of SK-7041 were due to apoptotic cell death caused by G2/M-phase arrest and to a lesser extent to G1 arrest. Moreover, SK-7041 inhibited cancer cell proliferation more selectively than NHBE cell proliferation.These results suggest that SK-7041 may have potential anticancer activity.

Histone acetyltransferase

Histone deacetylase inhibitor

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Citations (28)