Cancer is a complex disease characterized by the deregulation of normally balanced cell growth and survival pathways. Mutational alteration of specific oncogenes, such as PIK3CA and KRAS, can lead cancer cells to become dependent on their associated signaling pathways, a process known as oncogene addiction. As such, there has been a focused effort to develop inhibitors of major oncogenic pathways in cancer with the hypothesis that these drugs will cause tumor-specific cell death, ultimately leading to better outcomes in patients. However, intrinsic and acquired resistance to these so-called ?targeted therapies?, which is often driven by the activation of compensatory, or bypass, signaling mechanisms, limits their effectiveness by blocking drug- induced apoptosis (cell death). On the basis of these concepts, we hypothesized that we could improve the activity of targeted therapies by systematically identifying the pathways that drive resistance using high-throughput functional genomics approaches, coupled with mechanistic follow-up studies, and then leverage these insights to define combination therapies that drive potent and tumor-selective cell death. This project aims to characterize new dependencies, deemed ?collateral sensitivities?, in cancers that evolved resistance to a primary drug because these may be interesting therapeutic targets for patients that have already relapsed on a given targeted therapy. Collateral sensitivity is a concept that has been explored in detail in the microbial world. It is well established that once a bacterium becomes resistant to a given antibiotic, that bacterium often becomes hypersensitive to new antibiotics to which it was previously insensitive (collateral sensitivity). Reciprocally, that bacterium can also become resistant certain antibiotics to which it was previously sensitive (collateral resistance). There are many parallels between the fields of antibiotic resistance and resistance to targeted therapies in cancer; however, despite its potential clinical impact, there have not been any systematic efforts to study collateral sensitivity/resistance in diverse cancers.

Public Health Relevance

Cancer is a complex disease characterized by the deregulation of normally balanced cell growth and survival pathways. Deregulation of these pathways is often associated with new and targetable dependencies. This project aims to improve the activity of targeted therapies by systematically identifying these new dependencies using high-throughput functional genomics approaches.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Project #
4K00CA222728-03
Application #
9814740
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Eljanne, Mariam
Project Start
2017-09-15
Project End
2019-08-05
Budget Start
2019-01-01
Budget End
2019-08-05
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Stanford University
Department
Genetics
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305