Lung cancer is the leading cause of cancer death in the United States and world-wide, with over 85% of cases due to non-small cell lung cancer (NSCLC). The goal of our Program is to advance the pre-clinical science of NSCLC therapeutics. During the current funding period, our Program has advanced inhibitors of EGFR, promoting the pre-clinical development of osimertinib and related molecules, of TBK1, and of DDR2. In its next 5 years, our Program aims to develop compounds that will lead to more effective treatments for NSCLC and prevent or overcome resistance to existing and future targeted therapies. To accomplish these goals, the Program seeks to achieve the following overall aims via 3 inter-related and collaborative Projects and 4 intellectually driven Shared Resource Cores. --Overall Aim 1. Develop inhibitors and/or degraders focused on mutant EGFR, KRAS signaling effectors, and mechanisms of transcriptional adaptation in non-small cell lung cancer. --Overall Aim 2. Characterize these compounds and their targets pharmacologically using genetically defined cellular and animal models of lung cancer. --Overall Aim 3. Develop and assess combinations of these potent and selective novel agents with existing therapies to prevent and overcome therapeutic resistance.
These aims leverage innovations in chemistry and structural biology?the development of allosteric kinase inhibitors and selective degraders?coupled with expertise in lung cancer biology, lung cancer cellular and animal modeling, and functional genomic approaches to understanding pathways, through the Projects and Cores. The broad aims will be implemented with three focused projects aimed at developing inhibitors of key pathways in NSCLC as well as over-arching mechanisms of resistance: --Project 1: Development of pharmacologic strategies to degrade mutant EGFR. --Project 2: Identification of combination therapy for KRAS-driven lung cancers. --Project 3: Targeting transcriptional mechanisms of therapeutic resistance in non-small cell lung cancer. Each Project and the overall Program is based on the innovative, technology-driven Cores, each led by faculty with expertise in the specific areas. Core A: Medicinal Chemistry. Core B: Structure and Biochemistry. Core C: Animal Modeling and Preclinical Therapeutics. Core D: Program Administration. The integration of the three Projects and the four Cores will enable an effective co-ordination to meet Program aims by cross-fertilization of lung cancer focus and technological expertise.

Public Health Relevance

Lung cancer is the leading cause of cancer death world-wide. The purpose of our integrated research program is to discover information and create pilot molecules that will lead to new lung cancer treatments. During the past five years, we have advanced lung cancer treatments by promoting three new lung cancer clinical trials, one of which has led to approval of a new drug. During the next five years, we plan to build on this effort and further advance new lung cancer treatments.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Forry, Suzanne L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Dana-Farber Cancer Institute
United States
Zip Code
Deng, Jiehui; Wang, Eric S; Jenkins, Russell W et al. (2018) CDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation. Cancer Discov 8:216-233
Terai, Hideki; Kitajima, Shunsuke; Potter, Danielle S et al. (2018) ER Stress Signaling Promotes the Survival of Cancer ""Persister Cells"" Tolerant to EGFR Tyrosine Kinase Inhibitors. Cancer Res 78:1044-1057
Rusan, Maria; Li, Kapsok; Li, Yvonne et al. (2018) Suppression of Adaptive Responses to Targeted Cancer Therapy by Transcriptional Repression. Cancer Discov 8:59-73
Adeegbe, Dennis O; Liu, Shengwu; Hattersley, Maureen M et al. (2018) BET Bromodomain Inhibition Cooperates with PD-1 Blockade to Facilitate Antitumor Response in Kras-Mutant Non-Small Cell Lung Cancer. Cancer Immunol Res 6:1234-1245
Gannon, Hugh S; Zou, Tao; Kiessling, Michael K et al. (2018) Identification of ADAR1 adenosine deaminase dependency in a subset of cancer cells. Nat Commun 9:5450
Aguirre, Andrew J; Hahn, William C (2018) Synthetic Lethal Vulnerabilities in KRAS-Mutant Cancers. Cold Spring Harb Perspect Med 8:
Rowbotham, S P; Li, F; Dost, A F M et al. (2018) H3K9 methyltransferases and demethylases control lung tumor-propagating cells and lung cancer progression. Nat Commun 9:4559
Tan, Li; Gurbani, Deepak; Weisberg, Ellen L et al. (2017) Structure-guided development of covalent TAK1 inhibitors. Bioorg Med Chem 25:838-846
Tan, Li; Gurbani, Deepak; Weisberg, Ellen L et al. (2017) Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. Bioorg Med Chem 25:1320-1328
Adeegbe, Dennis O; Liu, Yan; Lizotte, Patrick H et al. (2017) Synergistic Immunostimulatory Effects and Therapeutic Benefit of Combined Histone Deacetylase and Bromodomain Inhibition in Non-Small Cell Lung Cancer. Cancer Discov 7:852-867

Showing the most recent 10 out of 80 publications