Receptor tyrosine kinases (RTKs) play a central role in regulation of cell response during development and homeostasis, and dysregulation contributes to diseases such as cancer. RTK-targeted therapies have been applied successfully in cancer treatment though with limited effectiveness as activity of non-targeted RTKs can enable cells to become resistant. While redundant signaling is now appreciated as a common mechanism of acquired and innate resistance, the exact signaling that is essential to resistance, and whether it is conserved or varies across cancer contexts, has not been addressed. RTKs lead to a common set of downstream signals, but in vastly different quantitative combinations, and differ in their ability to confer resistance in a context-dependent manner. A fundamental, rigorous understanding of resistance is necessary if we are to develop better therapies to overcome this redundancy. TAM receptors (Tyro3, AXL, MerTK) are a family of RTKs that have attracted interest for their widespread roles in tumor resistance and metastasis. However, while the ligands for these receptors have been identified, we lack even a basic understanding of the contexts that lead to activation of these receptors. RTKs work by auto- and trans-phosphorylation, recruiting adapter proteins, and then phosphorylating those adapters and other associated proteins. Systems biology has concentrated on easily measurable factors such as phosphorylation, but comparisons of signaling between receptors are not easily accomplished, as phosphosites between receptors do not readily equate. The amount of receptor-bound adapter molecules is one quantity that should be directly comparable however. Thus, I plan to develop techniques to measure RTK interaction quantitatively and across the multiple potential interactions within a cell simultaneously with the intention of more completely capturing signaling from these receptors. I will use these techniques combined with quantitative modeling to examine interactions during receptor activation and understand how different RTKs can provide redundant signaling leading to targeted cancer treatment resistance. These resistance and interaction models will then be applied to more specifically understand resistance conferred by the TAM family of RTKs. Through development of mechanistic models for ligand-dependent and independent signaling, linked to adapter interaction, downstream signaling, and tumor cell resistance, I plan to develop an integrative understanding of resistance. This will provide necessary information to develop therapies bypassing this problem.

Public Health Relevance

The proposed research is of immediate relevance to the public health mission of the NIH as it will considerably improve our understanding of resistance to targeted carcinoma therapies, which currently greatly limits their efficacy. This will focus development of new targeted drugs to overcome resistance, and accelerate study of future resistance mechanisms. The interaction methods developed will also have additional broad use for studying a variety of biological regulation.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
Early Independence Award (DP5)
Project #
1DP5OD019815-01
Application #
8795504
Study Section
Special Emphasis Panel (ZRG1-RPHB-W (53))
Program Officer
Basavappa, Ravi
Project Start
2014-09-22
Project End
2019-08-30
Budget Start
2014-09-22
Budget End
2015-08-30
Support Year
1
Fiscal Year
2014
Total Cost
$367,600
Indirect Cost
$117,600
Name
Massachusetts Institute of Technology
Department
Internal Medicine/Medicine
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Situ, Kathy; Chua, Bernadette Anne; Bae, Song Yi et al. (2018) Versatile targeting system for lentiviral vectors involving biotinylated targeting molecules. Virology 525:170-181
Robinett, Ryan A; Guan, Ning; Lux, Anja et al. (2018) Dissecting Fc?R Regulation through a Multivalent Binding Model. Cell Syst 7:41-48.e5
Schwartz, Alyssa D; Barney, Lauren E; Jansen, Lauren E et al. (2017) A biomaterial screening approach reveals microenvironmental mechanisms of drug resistance. Integr Biol (Camb) 9:912-924
Zweemer, Annelien J M; French, Cory B; Mesfin, Joshua et al. (2017) Apoptotic Bodies Elicit Gas6-Mediated Migration of AXL-Expressing Tumor Cells. Mol Cancer Res 15:1656-1666
Archer, Tenley C; Fertig, Elana J; Gosline, Sara J C et al. (2016) Systems Approaches to Cancer Biology. Cancer Res 76:6774-6777
Manole, Simin; Richards, Edward J; Meyer, Aaron S (2016) JNK Pathway Activation Modulates Acquired Resistance to EGFR/HER2-Targeted Therapies. Cancer Res 76:5219-28
Riquelme, Daisy N; Meyer, Aaron S; Barzik, Melanie et al. (2015) Selectivity in subunit composition of Ena/VASP tetramers. Biosci Rep 35:
Meyer, Aaron S; Zweemer, Annelien J M; Lauffenburger, Douglas A (2015) The AXL Receptor is a Sensor of Ligand Spatial Heterogeneity. Cell Syst 1:25-36