KRAS is a key regulatory component in a signaling pathway that involves upstream tyrosine kinase receptors (RTK), including EGFR, and downstream effector pathways regulated by RAF, phosphatidylinositol 3-kinase (PI3K) and Ral-GDS. Activating mutations of the KRAS proto- oncogene are present in ~30% of lung adenocarcinomas and are among the most common oncogenic mutations in human cancers. Although small molecule inhibitors of EGFR and other RTKs show clinical benefit in subsets of lung cancer patients, tumors that harbor KRAS mutations have proven refractory to both targeted and chemotherapeutic approaches, and despite intensive efforts, no effective therapies exist for KRAS mutated lung cancers. Thus, identifying therapeutic strategies to target lung and other human cancers that harbor KRAS mutations remains an important unsolved problem and an area of substantial clinical need. In the previous funding period, we investigated the non-canonical I?B kinase TBK1 as a target in KRAS-driven lung cancers. We elucidated the TBK1-regulated autocrine circuit that promotes the survival of KRAS-driven cancers, identified a small molecule TBK1/JAK inhibitor that inhibited the growth of KRAS-driven cancers in vivo, initiated a clinical trial involving the combination of this TBK1/JAK inhibitor with a clinically active MEK inhibitor, and identified mechanisms of resistance to KRAS-directed therapy. Based on the observation that oncogenic KRAS activates several pathways and transcriptional programs that conspire to drive cancer initiation and progression, we anticipate that combination strategies will be necessary to develop effective treatment regimens for KRAS- driven lung cancers. We propose to build on our preliminary studies to identify and credential complementary targets that will allow the development of rational combination therapies for KRAS-driven lung cancers. We will employ genetic, biochemical and pharmacologic approaches to eliminate c-RAF/MEK signaling, identify approaches to anticipate and target resistance mechanisms invoked by targeting KRAS effector pathways and develop combination therapies building on MEK and TBK1 inhibition. Specifically, we will use new technology to engender targeted degradation of c-RAF and MEK based on thalidomide-derivatized binders, and we will elucidate the role of, and develop therapies related to, the transcriptional regulators YAP1 and BRD4 in resistance to KRAS pathway inhibition. These studies will be performed in close collaboration with the other projects and cores of this Program and will inform the rational identification and development of effective combination therapies for KRAS-driven cancers.

Public Health Relevance

Although significant progress has been made in the diagnosis and treatment of lung cancer, we lack curative targeted therapies for most lung cancers. In particular, lung cancers that harbor oncogenic mutations in the KRAS oncogene are refractory to both cytotoxic and targeted chemotherapy. This proposal focuses on identifying the pathways that when targeted in combination lead to effective control of KRAS-driven lung cancers. These biochemical, cell and pharmacologic studies will serve as a foundation for translational studies for the development of novel therapeutic agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA154303-09
Application #
10003960
Study Section
Special Emphasis Panel (ZCA1)
Project Start
2012-05-11
Project End
2022-08-31
Budget Start
2020-09-01
Budget End
2021-08-31
Support Year
9
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
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