Mari Iida, PhD

Mari Iida, PhD

Associate Scientist

Department of Human Oncology

I am an associate scientist in the Wheeler Lab within the Department of Human Oncology. My research is focused on nuclear epidermal growth factor receptor (nEGFR) as a mediator of cetuximab (anti-EGFR antibody) resistance in triple negative breast cancer (TNBC). TNBC is a highly aggressive cancer with limited therapeutic options. Many studies have shown that ~50% of TNBC overexpress the oncogene EGFR and this predicts poor patient outcome. Unfortunately, clinical trials testing the efficacy of the cetuximab revealed little impact on outcomes in TNBC. It is well established that EGFR functions in two distinct signaling compartments: 1) Classical membrane-bound signaling and 2) nuclear signaling. Our lab has published data showing that nuclear EGFR (nEGFR) confers resistance to cetuximab therapy and that the Src Family Kinases (SFKs) are necessary for nuclear translocation of the EGFR. We would like to assess the therapeutic benefit of targeting both the classical and nEGFR signaling pathways simultaneously by abrogating nuclear translocation via SFK blockade (dasatinib) followed by blocking the classical EGFR signaling pathway with cetuximab. We are performing a window trial in nEGFR-positive TNBC patients currently, in order to determine if we can target nEGFR in humans and redistribute EGFR expression to the plasma membrane where it can be inhibited by cetuximab therapy. We hope our research will lead to rapid translation in TNBC patients harboring nuclear EGFR.

Education

Post-Doctoral Fellow, National Institute of Environmental Health Sciences, Molecular Carcinogenesis (2004)

PhD, University of Shizuoka, Nutritional and Environmental Sciences (2001)

BS, University of Shizuoka, Food and Nutritional Sciences (1993)

Academic Appointments

Associate Scientist, Human Oncology (2012)

Assistant Scientist, Human Oncology (2009)

Research Specialist, Human Oncology (2008)

Selected Honors and Awards

The 20th Annual Kitaji Mochizuki Young Scientist Award (2006)

Boards, Advisory Committees and Professional Organizations

Councilor, Japanese Toxicologic Pathology (2013–pres.)

Research Focus

Head and Neck Cancer, Triple Negative Breast Cancer, Non-Small Cell Lung Cancer

  • Correction: Nuclear Epidermal Growth Factor Receptor Is a Functional Molecular Target in Triple-negative Breast Cancer. Mol Cancer Ther
    Brand TM, Iida M, Dunn EF, Luthar N, Kostopoulos KT, Corrigan KL, Wleklinski MJ, Yang D, Wisinski KB, Salgia R, Wheeler DL
    2019 Apr; 18 (4): 868
  • Correction: AXL Is a Logical Molecular Target in Head and Neck Squamous Cell Carcinoma. Clin Cancer Res
    Brand TM, Iida M, Stein AP, Corrigan KL, Braverman CM, Coan JP, Pearson HE, Bahrar H, Fowler TL, Bednarz BP, Saha S, Yang D, Gill PS, Lingen MW, Saloura V, Villaflor VM, Salgia R, Kimple RJ, Wheeler DL
    2018 Dec 01; 24 (23): 6099
  • Corrigendum to: "Nuclear EGFR as a molecular target in cancer" [Radiother Oncol 108 (2013) 370-77]. Radiother Oncol
    Brand TM, Iida M, Luthar N, Starr MM, Huppert EJ, Wheeler DL
    2018 Nov 13; :
  • MERTK Mediates Intrinsic and Adaptive Resistance to AXL-targeting Agents. Mol Cancer Ther
    McDaniel NK, Cummings CT, Iida M, Hülse J, Pearson HE, Vasileiadi E, Parker RE, Orbuch RA, Ondracek OJ, Welke NB, Kang GH, Davies KD, Wang X, Frye SV, Earp HS, Harari PM, Kimple RJ, DeRyckere D, Graham DK, Wheeler DL
    2018 11; 17 (11): 2297-2308
    • More

      The TAM (TYRO3, AXL, MERTK) family receptor tyrosine kinases (RTK) play an important role in promoting growth, survival, and metastatic spread of several tumor types. AXL and MERTK are overexpressed in head and neck squamous cell carcinoma (HNSCC), triple-negative breast cancer (TNBC), and non-small cell lung cancer (NSCLC), malignancies that are highly metastatic and lethal. AXL is the most well-characterized TAM receptor and mediates resistance to both conventional and targeted cancer therapies. AXL is highly expressed in aggressive tumor types, and patients with cancer are currently being enrolled in clinical trials testing AXL inhibitors. In this study, we analyzed the effects of AXL inhibition using a small-molecule AXL inhibitor, a monoclonal antibody (mAb), and siRNA in HNSCC, TNBC, and NSCLC preclinical models. Anti-AXL-targeting strategies had limited efficacy across these different models that, our data suggest, could be attributed to upregulation of MERTK. MERTK expression was increased in cell lines and patient-derived xenografts treated with AXL inhibitors and inhibition of MERTK sensitized HNSCC, TNBC, and NSCLC preclinical models to AXL inhibition. Dual targeting of AXL and MERTK led to a more potent blockade of downstream signaling, synergistic inhibition of tumor cell expansion in culture, and reduced tumor growth in vivo Furthermore, ectopic overexpression of MERTK in AXL inhibitor-sensitive models resulted in resistance to AXL-targeting strategies. These observations suggest that therapeutic strategies cotargeting both AXL and MERTK could be highly beneficial in a variety of tumor types where both receptors are expressed, leading to improved survival for patients with lethal malignancies. Mol Cancer Ther; 17(11); 2297-308. ©2018 AACR.

      View details for PubMedID 30093568
  • Akt1 and Akt3 but not Akt2 through interaction with DNA-PKcs stimulate proliferation and post-irradiation cell survival of K-RAS-mutated cancer cells. Cell Death Discov
    Toulany M, Maier J, Iida M, Rebholz S, Holler M, Grottke A, Jüker M, Wheeler DL, Rothbauer U, Rodemann HP
    2017; 3: 17072
    • More

      Akt1 through the C-terminal domain interacts with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and stimulates the repair of DNA double-strand breaks (DSBs) in K-RAS-mutated (K-RASmut) cells. We investigated the interactions of distinct domain(s) of DNA-PKcs in binding to full-length Akt1. Similarly, we analyzed potential interactions of DNA-PKcs with Akt2 and Akt3. Finally the effect of Akt isoforms in cell proliferation and tumor growth was tested. We demonstrated that Akt1 preferentially binds to the N-terminal domain of DNA-PKcs using pull-down studies with distinct eGFP-tagged DNA-PKcs fragments that were expressed by plasmids in combination with mCherry-tagged full-length Akt isoforms. These binding studies also indicated an interaction with the intermediate and C-terminal domains of DNA-PKcs. In contrast, Akt3 interacted with all four DNA-PKcs fragments without a marked preference for any specific domain. Notably, we could not see binding of Akt2 to any of the tested DNA-PKcs fragments. In subsequent studies, we demonstrated that Akt inhibition interferes with binding of Akt1 to the N-terminal domain of DNA-PKcs. This indicated a correlation between Akt1 activity and the Akt1/DNA-PKcs complex formation. Finally, knockdown studies revealed that the depletion of endogenous Akt1 and Akt3, but not Akt2, inhibit clonogenic activity and repair of ionizing radiation (IR)-induced DNA DSBs, leading to radiosensitization. Furthermore, in a xenograft study the expression of shAkt1 or shAkt3, but not shAkt2 in K-RASmut breast cancer cell line MDA-MB-231 showed major tumor growth delay. Together, these data indicate that Akt1 and Akt3, but not Akt2, physically interact with DNA-PKcs, thus stimulating the repair of DSBs and therefore protecting K-RASmut cells against IR. Likewise, interaction of Akt isoforms with DNA-PKcs could be crucial for their role in regulating tumor growth.

      View details for PubMedID 29090098
  • Overcoming Resistance to Cetuximab with Honokiol, A Small-Molecule Polyphenol. Mol Cancer Ther
    Pearson HE, Iida M, Orbuch RA, McDaniel NK, Nickel KP, Kimple RJ, Arbiser JL, Wheeler DL
    2018 01; 17 (1): 204-214
    • More

      Overexpression and activation of the EGFR have been linked to poor prognosis in several human cancers. Cetuximab is a mAb against EGFR that is used for the treatment in head and neck squamous cell carcinoma (HNSCC) and metastatic colorectal cancer. Unfortunately, most tumors have intrinsic or will acquire resistance to cetuximab during the course of therapy. Honokiol is a natural compound found in the bark and leaves of the Chinese Magnolia tree and is established to have several anticancer properties without appreciable toxicity. In this study, we hypothesized that combining cetuximab and honokiol treatments could overcome acquired resistance to cetuximab. We previously developed a model of acquired resistance to cetuximab in non-small cell lung cancer H226 cell line. Treatment of cetuximab-resistant clones with honokiol and cetuximab resulted in a robust antiproliferative response. Immunoblot analysis revealed the HER family and their signaling pathways were downregulated after combination treatment, most notably the proliferation (MAPK) and survival (AKT) pathways. In addition, we found a decrease in phosphorylation of DRP1 and reactive oxygen species after combination treatment in cetuximab-resistant clones, which may signify a change in mitochondrial function. Furthermore, we utilized cetuximab-resistant HNSCC patient-derived xenografts (PDX) to test the benefit of combinatorial treatment in vivo There was significant growth delay in PDX tumors after combination treatment with a subsequent downregulation of active MAPK, AKT, and DRP1 signaling as seen in vitro Collectively, these data suggest that honokiol is a promising natural compound in overcoming acquired resistance to cetuximab. Mol Cancer Ther; 17(1); 204-14. ©2017 AACR.

      View details for PubMedID 29054984
  • Cotargeting mTORC and EGFR Signaling as a Therapeutic Strategy in HNSCC. Mol Cancer Ther
    Swick AD, Prabakaran PJ, Miller MC, Javaid AM, Fisher MM, Sampene E, Ong IM, Hu R, Iida M, Nickel KP, Bruce JY, Wheeler DL, Kimple RJ
    2017 Jul; 16 (7): 1257-1268
    • More

      Head and neck squamous cell carcinomas (HNSCC) are frequently altered along the PI3K/AKT/mTORC signaling axis. Despite excellent preclinical data, the use of compounds targeting this pathway as monotherapy has been underwhelming in initial clinical trials, and identification of predictive biomarkers remains challenging. To investigate mTORC-specific inhibition, we tested catalytic mTORC (AZD8055) and PI3K/mTORC (NVP-BEZ-235) inhibitors ± cetuximab in a panel of HNSCC cell lines and patient-derived xenografts (PDX). Cell lines were assayed for response to all agents and siRNA knockdown of targets by multiple approaches. All cell lines showed similar response to both drug and siRNA inhibition of both PI3K and mTORC pathways, with anti-EGFR combination producing modest additive effect. Five PDX models that presented PIK3CA mutation or intrinsic cetuximab resistance were treated with a combination of cetuximab and AZD8055. In vivo single-agent mTORC inhibition inhibited growth of one PIK3CA-mutant cancer, but had little effect on any PIK3CAWT or a second PIK3CA-mutant model. In all models, the combination therapy showed greater growth delay than monotherapy. The uniform ability of PI3K and mTORC inhibition to suppress the growth of HNSCC cells highlights the pathway's role in driving proliferation. Although single-agent therapy was largely ineffective in vivo, improved response of combination treatment in an array of PDXs suggests the potential for adding a catalytic mTORC inhibitor to cetuximab therapy. Overall, these results add to a growing body of evidence, suggesting that approaches that attempt to match biomarkers to the optimal therapy in HNSCC remain complex and challenging. Mol Cancer Ther; 16(7); 1257-68. ©2017 AACR.

      View details for PubMedID 28446642
  • The receptor tyrosine kinase AXL mediates nuclear translocation of the epidermal growth factor receptor. Sci Signal
    Brand TM, Iida M, Corrigan KL, Braverman CM, Coan JP, Flanigan BG, Stein AP, Salgia R, Rolff J, Kimple RJ, Wheeler DL
    2017 Jan 03; 10 (460):
    • More

      The epidermal growth factor receptor (EGFR) is a therapeutic target in patients with various cancers. Unfortunately, resistance to EGFR-targeted therapeutics is common. Previous studies identified two mechanisms of resistance to the EGFR monoclonal antibody cetuximab. Nuclear translocation of EGFR bypasses the inhibitory effects of cetuximab, and the receptor tyrosine kinase AXL mediates cetuximab resistance by maintaining EGFR activation and downstream signaling. Thus, we hypothesized that AXL mediated the nuclear translocation of EGFR in the setting of cetuximab resistance. Cetuximab-resistant clones of non-small cell lung cancer in culture and patient-derived xenografts in mice had increased abundance of AXL and nuclear EGFR (nEGFR). Cellular fractionation analysis, super-resolution microscopy, and electron microscopy revealed that genetic loss of AXL reduced the accumulation of nEGFR. SRC family kinases (SFKs) and HER family ligands promote the nuclear translocation of EGFR. We found that AXL knockdown reduced the expression of the genes encoding the SFK family members YES and LYN and the ligand neuregulin-1 (NRG1). AXL knockdown also decreased the interaction between EGFR and the related receptor HER3 and accumulation of HER3 in the nucleus. Overexpression of LYN and NRG1 in cells depleted of AXL resulted in accumulation of nEGFR, rescuing the deficit induced by lack of AXL. Collectively, these data uncover a previously unrecognized role for AXL in regulating the nuclear translocation of EGFR and suggest that AXL-mediated SFK and NRG1 expression promote this process.

      View details for PubMedID 28049763
  • Dual targeting of PI3K and MEK enhances the radiation response of K-RAS mutated non-small cell lung cancer. Oncotarget
    Toulany M, Iida M, Keinath S, Iyi FF, Mueck K, Fehrenbacher B, Mansour WY, Schaller M, Wheeler DL, Rodemann HP
    2016 Jul 12; 7 (28): 43746-43761
    • More

      Despite the significant contribution of radiotherapy to non-small lung cancer (NSCLC), radioresistance still occurs. One of the major radioresistance mechanisms is the hyperactivation of the PI3K/Akt pathway in which Akt facilitates the repair of DNA double-strand breaks (DSBs) through the stimulation of DNA-PKcs. We investigated if targeting PI3K would be a potential approach for enhancing the radiosensitivity of K-RAS mutated (K-RASmut) NSCLC cell lines A549 and H460. Short-term (1-2 h) pre-treatment of cells with the PI3K inhibitor PI-103 (1 μM) inhibited Akt/DNA-PKcs activity, blocked DSBs repair and induced radiosensitivity, while long-term (24 h) pre-treatment did not. Lack of an effect after 24 h of PI-103 pre-treatment was due to reactivation of K-Ras/MEK/ERK-dependent Akt. However, long-term treatment with the combination of PI-103 and MEK inhibitor PD98059 completely blocked reactivation of Akt and impaired DSBs repair through non-homologous end joining (NHEJ) leading to radiosensitization. The effect of PI3K inhibition on Akt signaling was also tested in A549 mouse xenografts. P-Akt and P-DNA-PKcs were inhibited 30 min post-irradiation in xenografts, which were pretreated by PI-103 30 min before irradiation. However, Akt was reactivated 30 min post-irradiation in tumors, which were pre-treated for 3 h with PI-103 before irradiation. After a 24 h pretreatment with PI-103, a significant reactivation of Akt was achieved 24 h after irradiation. Thus, due to MEK/ERK-dependent reactivation of Akt, targeting PI3K alone is not a suitable approach for radiosensitizing K-RASmut NSCLC cells, indicating that dual targeting of PI3K and MEK is an efficient approach to improve radiotherapy outcome.

      View details for PubMedID 27248324

Contact Information

Mari Iida, PhD

1111 Highland Avenue,
3136 WIMR
Madison, WI 53705
Email