Aaron Hata

Hata Lab

The Hata laboratory focuses on understanding the biological underpinnings of sensitivity and resistance to kinase inhibitor targeted therapies in lung cancers with specific genetic abnormalities (EGFR mutations, ALK translocations, KRAS mutations).

Overview

Aaron Hata, MD, PhD

Assistant Professor of Medicine
Harvard Medical School

Assistant Physician
Hematology and Oncology at the Massachusetts General Hospital

Research Summary

The research goal of the Hata laboratory is to advance targeted therapies to benefit patients with lung cancer. Our research focuses on understanding the biological underpinnings of sensitivity and resistance to kinase inhibitor targeted therapies in lung cancers with specific genetic abnormalities (EGFR mutations, ALK translocations, KRAS mutations, etc.). In particular, we seek to understand how kinase inhibitors modulate signaling networks that regulate cancer cell growth and survival, and characterize the molecular mechanisms of acquired resistance to these agents. More recently, we have begun to focus on understanding how cancer cells adapt and evolve during the course of therapy in order to identify vulnerabilities of drug tolerant cancer cells that might be exploited to prevent resistance from developing. Our studies are highly translational, combining cell culture models, patient-derived mouse (PDX) models and assessment of clinical specimens, and are performed in close collaboration with clinicians in the Thoracic Oncology group.

Read the Hata Lab Report in Full

Group Members

Aaron Hata, MD, PhD
Principal Investigator

Group members:

  • Ammal Abbasi
  • Kankana Bardhan, PhD
  • Samantha Bilton
  • Leila Dardaei, PhD
  • Heidie Frisco-Cabanos, PhD
  • Aaron Hata, MD, PhD
  • Haichuan Hu, MD
  • Hideko Isozaki, PhD
  • Chendi Li, PhD
  • Varuna Nangia
  • Kylie Prutisto-Chang
  • Sana Raoof
  • Kathy Shaw
  • Daria Timonina
  • Satoshi Yoda, MD

Research Projects

EGFR

EGFR inhibitors have revolutionized the treatment of EGFR mutant non-small cell lung cancer (NSCLC), with patients achieving robust responses. Unfortunately, drug resistance invariably occurs, and patients typically relapse after one year of treatment. Next generation EGFR inhibitors that overcome the most common resistance mutation, EGFRT790M, have now entered the clinic, but ultimately resistance to these agents also occurs. We recently demonstrated that resistance due to acquisition of the EGFRT790M mutation can arise via evolution of drug tolerant clones that survive initial therapy and then acquire the mutation. This suggests that drug tolerant cells that survive initial EGFR inhibitor therapy may comprise a cellular reservoir from which heterogeneous mechanisms of resistance may arise. We are currently performing single cell analysis and multi-dimensional profiling of patient tumor specimens and PDX models before, during and after treatment in order to understand the genetic, epigenetic and micro-environmental mechanisms that contribute to the evolution of acquired drug resistance in vivo. By identifying vulnerabilities of drug tolerant cells prior to development of resistance, we hope to develop novel therapeutic strategies that will disrupt this perpetual cycle of acquired resistance.

EGFR mutant lung cancers can develop acquired resistance to EGFR inhibitors (e.g. acquisition of the gatekeeper EGFRT790M mutation) by selection of pre-existing EGFRT790M cells or via evolution of initially EGFRT790M-negative drug tolerant cells that then develop the mutation during the course of treatment. EGFRi denotes EGFR inhibitor treatment, such as gefitinib or erlotinib. Reproduced from Hata and Niederst, et al. Nature Medicine 2016.

 

ALK

Anaplastic lymphoma kinase (ALK) gene rearrangements have emerged as well-established oncogenic drivers and therapeutic targets in NSCLC. Several successive generations of ALK inhibitors have now entered the clinic, and ALK-dependent and ALK-independent resistance mechanisms have been identified. By interrogating in vitro and in vivo models of acquired resistance to ALK inhibitors, including cell lines and PDX models established from biopsies of patients at the time of disease progression, we are uncovering novel mechanisms of acquired resistance and developing treatment strategies to overcome them. Additionally, we are interested in understanding the impact of intra- and intertumoral heterogeneity on drug response and acquired resistance to ALK inhibitors. By monitoring clonal evolution over time through analysis of serial tumor biopsies and circulating cell free tumor DNA, we hope to better tailor ALK inhibitor therapies to individual patients.

KRAS

KRAS is the most common driver oncogene in lung cancer and development of therapeutic strategies to improve the survival of these patients represents one of the most important needs in all of oncology. We are exploring multiple strategies to develop effective therapies for KRAS mutant lung cancer. First, we are testing novel agents that directly inhibit mutant KRAS. Second, we are exploring how drugs that directly target apoptotic regulators such as BCL-2 family proteins may enhance the efficacy of kinase inhibitors to induce apoptosis in KRAS mutant lung cancer. Third, we are exploring how targeted therapies and immunotherapies can be integrated in order to induce long term remissions in patients with KRAS mutant lung cancer. We believe this latter approach will set a new standard for understanding how interactions between oncoprotein-activated pathways and the immune microenvironment regulate tumor growth.

Select Publications

Hata AN, Rowley S, Archibald HL, Gomez-Caraballo M, Siddiqui FM, Ji F, Jung J, Light M, Lee JS, Debussche L, Sidhu S, Sadreyev RI, Watters J, Engelman JA. Synergistic activity and heterogeneous acquired resistance of combined MDM2 and MEK inhibition in KRAS mutant cancers. Oncogene. 2017, in press.

Hata AN, Niederst MJ, Archibald HL, Gomez-Caraballo M, Siddiqui FM, Mulvey HE, Maruvka YE, Ji F, Bhang HC, Radhakrishna VK, Siravegna G, Hu H, Raoof S, Lockerman E, Kalsy A, Lee D, Keating CL, Ruddy DA, Damon LJ, Crystal AS, Costa C, Piotrowska Z, Bardelli A, Iafrate AJ, Sadreyev RI, Stegmeier F, Getz G, Sequist LV, Faber AC, Engelman, JA. Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nature Medicine. 2016; 22:262-9.

Gainor JF, Shaw AT, Sequist LV, Fu X, Azzoli CG, Piotrowska P, Huynh TG, Zhao L, Fulton L, Schultz K, Howe E, Farago AF, Sullivan RJ, Stone JR, Digumarthy S, Moran T, Hata AN, Yagi Y, Yeap BY, Engelman JA, Mino-Kenudson M. EGFR Mutations and ALK Rearrangements Are Associated with Low Response Rates to PD-1 Pathway Blockade in Non-Small Cell Lung Cancer (NSCLC): A Retrospective Analysis. Clin Cancer Res. 2016;22:4585-93.

Piotrowska Z, Niederst MJ, Karlovich CA, Wakelee HA, Neal JW, Mino-Kenudson M, Fulton L, Hata AN, Lockerman EL, Kalsy A, Digumarthy S, Muzikansky A, Raponi M, Garcia AR, Mulvey HE, Parks MK, DiCecca RH, Dias-Santagata D, Iafrate AJ, Shaw AT, Allen AR, Engelman JA, Sequist LV. Heterogeneity Underlies the Emergence of EGFR T790 Wild-Type Clones Following Treatment of T790M-Positive Cancers with a Third Generation EGFR Inhibitor. Cancer Discov. 2015; 5:713-22.

Hata AN, Yeo A, Faber AC, Lifshits E, Chen Z, Cheng KA, Walton Z, Sarosiek KA, Letai A, Heist RS, Mino-Kenudson M, Wong KK, Engelman JA. Failure to induce apoptosis via BCL-2 family proteins underlies lack of efficacy of combined MEK and PI3K inhibitors for KRAS-mutant lung cancers. Cancer Research. 2014;74:3146-56.

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