Over, the past several years, we have learned that subsets of genetically defined cancers require an activated kinase for their growth and survival. In these cancers, the kinase is often directly activated by genetic alteration;mutation, amplification or translocation. These cancer cells are "addicted" to the genetically activated kinase, and they die, via apoptosis, upon inhibition of the kinase. This is known as "targeted therapy." These findings have already had a transformative impact on cancer therapeutics. In 2009, Massachusetts General Hospital (MGH) created a Translational Research Laboratory to perform multiplexed genetic analyses on the lung cancers of all patients being treated at MGH, and we have genotyped over 600 cases in the past year. This technology is quickly being implemented at many other cancer centers throughout the country, highlighting the importance of this burgeoning field. Intriguingly, while many of these genetically defined cancers (such as EGFR mutant and ALK translocated) have dramatic responses following targeted therapies, some have either poor responses or no responses, for largely unknown reasons. While resistance in some of these cancers are thought to be caused by secondary mutations that result in sustained intracellular signaling in the presence of targeted therapy, a large population of patients, whom do not carry these mutations in their cancers, are resistant for unknown reasons. We have found that targeted therapies are most effective when they induce both growth arrest and cell death (apoptosis). When they fail to, responses are mitigated. The inadequacy of targeted therapies to induce apoptosis may be caused by a deficiency in the pro-apoptotic protein, BIM. In this application, we propose that, in the setting of oncogene addiction, resistance arises when targeted therapies fail to induce apoptosis in oncogene-addicted cancers, despite downregulation of the intracellular signaling and posit that these cancers fail to undergo apoptosis because of deficiencies in the expression of BIM. We highlight preliminary data that supports these hypotheses, including functional in vitro and in vivo analyses, predictive power of BIM expression to apoptosis in cell line models, and patient data suggesting BIM expression can prospectively predict patient response to EGFR mutant targeted therapies. Lastly, we discuss potential, testable pharmaceutical strategies to overcome BIM deficiency in these cancers. If our testable hypothesis is proven correct, determining BIM expression in pre-treatment levels of oncogene- addicted cancers will change the way this growing population of cancer patients is treated.

Public Health Relevance

Targeted therapies directed against kinases can be highly effective in a subset of genetically defined cancers, such as epidermal growth factor receptor EGFR mutant and HER2 amplified breast cancers. Yet, even amongst genetically distinct oncogene-addicted models of cancers, there is a confounding gradient of response to targeted therapy ranging from complete response to progressive disease;cancers which fall towards the end of this spectrum are said to have relative intrinsic resistance. The experiments highlighted in this proposal, based on preliminary data, aim to prove that deficiency of the pro-apoptotic protein BIM, both causes and predicts relative intrinsic resistance to targeted therapies in these cancers. The written critiques and criteria scores of individual reviewers are provided in essentially unedited form in the Critique section below. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The Resume and Summary of Discussion section above summarizes the final opinions of the committee.

Agency
National Institute of Health (NIH)
Type
Career Transition Award (K22)
Project #
1K22CA175276-01
Application #
8487925
Study Section
Subcommittee B - Comprehensiveness (NCI)
Program Officer
Jakowlew, Sonia B
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298