Division of Molecular Therapeutics

• Introduction
• Research topics
• Members
• Publications
• Education & Training

Introduction

We have been focusing on developing effective therapies against cancers with aberrant MPAK activation, especially caused by RAS/RAF mutations. We also aim to expand the molecular classification of colorectal cancer by integrating ctDNA analysis results, whole exome and RNA sequencing data.

Research topics

Resistance Mechanism to KRAS inhibitors

KRAS mutations are commonly observed in cancers. The relatively smooth surface architecture of RAS and its picomolar affinity for GTP/GDP have given rise to the assumption that RAS is “undruggable”. However, recent identification of a pocket in its switch II region has allowed targeting of tumors with the KRAS G12C mutation. While the observed responses in KRAS-mutant patients, especially with lung cancer, are encouraging, the response rate is low compared with other drugs targeting driver oncogenes such as EGFR and ALK inhibitors. We have elucidated that tumor cells can acquire mutant KRAS independence by activating pathways that functionally substitute for the mutant KRAS. These KRAS-independent tumor cells exhibit a mesenchymal phenotype, readily primed for potential metastasis. Activation of YAP and mutations in LKB1, KEAP1, and/or NRF2, associated with mutant KRAS autonomy, rewire survival signaling and metabolic processes. The presence of KRAS-independent cells is associated with the heterogeneity of KRAS mutant cancers, as well as variable responses to therapies. Notably, KRAS G12C-specific inhibitors appear to be effective only in tumors dependent on mutant KRAS for their survival. Therefore, determining KRAS dependence will be critical for selecting patients who should be treated with mutant-specific inhibitors. Furthermore, elucidating underlying mechanisms of KRAS autonomy is crucial for developing optimal treatment strategies for KRAS-independent tumors.

Mutli-omics analysis for colorectal cancer: integrating the results of circulating tumor DNA, exome and transcriptome analyses

The current standard of care for patients with colorectal cancer includes surgical resection followed by adjuvant chemotherapy. All stage III and pathologically assessed high-risk stage II patients are treated with 5-FU based chemotherapy. However, more than half are estimated to be free from risk of recurrence even without adjuvant chemotherapy. Therefore, identification of predictive markers for recurrence is necessary to avoid unnecessary treatment and reduce medical costs. In addition, molecular targets for patients demonstrating relapse despite receiving adjuvant chemotherapy are a high priority. The detection of circulating tumor DNA in blood is a relatively non-invasive method that may help genotyping, selection of treatment options, and monitoring response to treatment. To investigate the potential use of ctDNA markers for detecting residual disease to predict who is at high risk of relapse, and using ctDNA assay as a guide for adjuvant chemotherapy, a multicenter investigator-initiated trial, CIRCULATE-Japan, was launched in May 2020 and  more than 4000 patients who have undergone curative surgery for colorectal cancer have been prospectively enrolled. Our laboratory has responsibility for translational research within this project, integrating ctDNA, mutational, and RNA sequencing analyses to identify molecular subtypes and new molecular targets. Our twin goal is to establish biomarkers to stratify patients who do not require adjuvant chemotherapy and identify molecular targets to enhance the efficacy of adjuvant chemotherapy.

Members

Publications

• 2022
• 2021
• 2020
• 2019 selected
• 2018 selected

2022

1. Cai J, Jacob S, Kurupi R, Dalton KM, Coon C, Greninger P, Egan RK, Stein GT, Murchie E, McClanaghan J, Adachi Y, Hirade K, Dozmorov M, Glod J, Boikos SA, Ebi H, Hao H, Caponigro G, Benes CH, Faber AC. High-risk neuroblastoma with NF1 loss of function is targetable using SHP2 inhibition. Cell Reports, 40:111095, 2022
2. Su, WJ; Mukherjee, R; Yaeger, R; Son, J; Xu, JN; Na, N; Timaul, NM; Hechtman, J; Paroder, V; Lin, M; Mattar, M; Qiu, J; Chang, Q; Zhao, HY; Zhang, J; Little, M; Adachi, Y; Han, SW; Taylor, BS; Ebi, H; Abdel-Wahab, O; de Stanchina, E; Rudin, CM; Janne, PA; McCormick, F; Yao, Z; Rosen, N. ARAF protein kinase activates RAS by antagonizing its binding to RASGAP NF1. Molecular Cell, 82:2443-2457, 2022.
3. Vega P.N., Nilsson A., Kumar M.P., Niitsu H., Simmons A.J., Ro J., Wang J., Chen Z., Joughin B.A., Li W., McKinley E.T., Liu Q., Roland J.T., Washington M.K., Coffey R.J., Lauffenburger D.A., and Lau K.S. Cancer-Associated Fibroblasts and Squamous Epithelial Cells Constitute a Unique Microenvironment in a Mouse Model of Inflammation-Induced Colon Cancer. Front Oncol,12;878920, 2022.

2021

4. Escaping KRAS: Gaining Autonomy and Resistance to KRAS Inhibition in KRAS Mutant Cancers. Cancers. 13:5081, 2021.
5. Nakamura, Y; Okamoto, W; Kato, T; Esaki, T; Kato, K; Komatsu, Y; Yuki, S; Masuishi, T; Nishina, T; Ebi, H; Sawada, K; Taniguchi, H; Fuse, N; Nomura, S; Fukui, M; Matsuda, S; Sakamoto, Y; Uchigata, H; Kitajima, K; Kuramoto, N; Asakawa, T; Olsen, S; Odegaard, JI; Sato, A; Fujii, S; Ohtsu, A; Yoshino, T. Circulating tumor DNA-guided treatment with pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer: a phase 2 trial. Nature Med. 27:1899-1903, 2021.
6. Nakasuka, F; Tabata, S; Sakamoto, T; Hirayama, A; Ebi, H; Yamada, T; Umetsu, K; Ohishi, M; Ueno, A; Goto, H; Sugimoto, M; Nishioka, Y; Yamada, Y; Tomita, M; Sasaki, AT; Yano, S; Soga, T. TGF-beta-dependent reprogramming of amino acid metabolism induces epithelial-mesenchymal transition in non-small cell lung cancers. Communications Biology, 4:782, 2021.
7. Taniguchi, H; Nakamura, Y; Kotani, D; Yukami, H; Mishima, S; Sawada, K; Shirasu, H; Ebi, H; Yamanaka, T; Aleshin, A; Bllings, PR; Rabinowitz, M; Oki, E; Takemasa, I; Kato, T; Mori, M; Yoshino, T. CIRCULATE-Japan: Circulating tumor DNA-guided adaptive platform trials to refine adjuvant therapy for colorectal cancer. Cancer Science, 112:2915-2920, 2021.
8. Niitsu H., Lu Y., Huh W.J., Love A.M., Franklin J.L., and Coffey R.J., Cell-Autonomous Role of EGFR in Spontaneous Duodenal Tumors in LRIG1 Null Mice. Cell Mol Gastroenterol Hepatol, 12: 1159-1162, 2021.
9. Chen B., Scurrah C.R., McKinley E.T., Simmons A.J., Ramirez-Solano M.A., Zhu X., Markham N.O., Heiser C.N., Vega P.N., Rolong A., Kim H., Sheng Q., Drewes J.L., Zhou Y., Southard-Smith A.N., Xu Y., Ro J., Jones A.L., Revetta F., Berry L.D., Niitsu H., Islam M., Pelka K., Hofree M., Chen J.H., Sarkizova S., Ng K., Giannakis M., Boland G.M., Aguirre A.J., Anderson A.C., Rozenblatt-Rosen O., Regev A., Hacohen N., Kawasaki K., Sato T., Goettel J.A., Grady W.M., Zheng W., Washington M.K., Cai Q., Sears C.L., Goldenring J.R., Franklin J.L., Su T., Huh W.J., Vandekar S., Roland J.T., Liu Q., Coffey R.J., Shrubsole M.J., and Lau K.S., Differential pre-malignant programs and microenvironment chart distinct paths to malignancy in human colorectal polyps. Cell, 184:6262-6280, 2021.

2020

10. Adachi, Y; Ito, K; Hayashi, Y; Kimura, R; Tan, TZ; Yamaguchi, R; Ebi, H. Epithelial-to-Mesenchymal Transition is a Cause of Both Intrinsic and Acquired Resistance to KRAS G12C Inhibitor in KRAS G12C-Mutant Non-Small Cell Lung Cancer. Clinical Cancer Res, 26:5962-5973, 2020.
11. Costa C, Wang Y, Ly A, Hosono Y, Ellen M, Walmsley CS, Huynh T, Healy C, Peterson R, Yanase S, Jakubik CT, Henderson LE, Damon LJ, Timonina D, Sanidas I, Pinto CJ, Mino-Kenudson M, Stone JR, Dyson NJ, Ellisen LW, Bardia A, Ebi H, Benes CH, Engelman JA and Juric D. PTEN loss mediates clinical cross-resistance to CDK4/6 and PI3Kalpha inhibitors in breast cancer. Cancer Discov. 10, 72-85, 2020.
12. Ebi H, Bando H, Taniguchi H, Sunakawa Y, Okugawa Y, Hatanaka Y, Hosoda W, Kumamoto K, Nakatani K, Yamazaki K. Japanese Society of Medical Oncology Clinical Guidelines: Molecular Testing for Colorectal Cancer Treatment, 4th edition. Cancer Sci. 111:3962-3969, 2020
13. Huh W.J., Niitsu H., Carney B., McKinley E.T., Houghton J.L., and Coffey R.J., Identification and Characterization of Unique Neutralizing Antibodies to Mouse EGF Receptor. Gastroenterology, 158: 1500-1502, 2020.

2019 selected

14. Yaeger R, Kotani D, Mondaca S, Parikh AR, Bando H, Van Seventer EE, Taniguchi H, Zhao H, Thant CN, de Stanchina E, Rosen N, Corcoran RB, Yoshino T, Yao Z and Ebi H. Response to Anti-EGFR Therapy in Patients with BRAF non-V600-Mutant Metastatic Colorectal Cancer. Clin Cancer Res. 25:7089-7097, 2019.

2018 selected

15. Song KA, Hosono Y, Turner C, Jacob S, Lochmann TL, Murakami Y, Patel NU, Ham J, Hu B, Powell KM, Coon CM, Windle BE, Oya Y, Koblinski JE, Harada H, Leverson JD, Souers AJ, Hata AN, Boikos S, Yatabe Y, Ebi H* and Faber AC*. Increased Synthesis of MCL-1 Protein Underlies Initial Survival of EGFR-Mutant Lung Cancer to EGFR Inhibitors and Provides a Novel Drug Target. Clin Cancer Res. 24:5658-5672, 2018. (*Co-corresponding author)
16. Kotani H, Adachi Y, Kitai H, Tomida S, Bando H, Faber AC, Yoshino T, Voon DC, Yano S and Ebi H. Distinct dependencies on receptor tyrosine kinases in the regulation of MAPK signaling between BRAF V600E and non-V600E mutant lung cancers. Oncogene. 37:1775-1787, 2018.

Education & Training

Positions for Ph.D. students and Postdoctoral Fellows

Postdoctoral positions are available for highly motivated candidates with a background in molecular and cellular biology to join our lab. The focus of our laboratory research program is to investigate the molecular mechanisms of dysregulated cellular signaling in pathways playing critical roles in tumor cell survival. For this purpose, we inhibit activity of molecules of interest using small molecule inhibitors, knock out/down or overexpression. Results of our research are being translated into clinical settings.