Mechanisms underlying cellular addiction to HER2
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: The simplest understanding of oncogenes such as HER2 has been that they turn on and cause the malignant behavior of cancer cells and propel tissue invasion, metastasis, and death. But HER2 is turned on at very early stages of tumorigenesis such as DCIS which has no ability to invade, metastasize, or cause death. So obviously there is something wrong with the hypothesis that HER2 overactivity is directly responsible for the lethal biology of these cancers. 
 We have made the novel discovery that there is a second distinct step following HER2 transformation, a step called HER2 addiction, which we believe is linked with the aggressive biology and lethality of these cancers. If we can understand the molecular mechanisms responsible for this second step, we can potentially develop treatments that interfere with this aggressive step; treatments that may reverse the lethal phenotype of these cancers, much more profoundly than current drugs targeting HER2. Or we can potentially develop treatments that when combined with current HER2 inhibitors produce highly effective anti-cancer therapies. 
 The question(s) or central hypotheses of the research: We think the biology of HER2-amplified breast cancers can be profoundly altered, even in very advanced stages by targeting the second step in HER2-driven tumorigenesis rather than HER2 itself. It is difficult to know exactly what the affects of such an alteration will be, but it could be that advanced HER2 positive cancers will stop growing and be rendered inert and non-lethal, or perhaps these tumors would die, or perhaps they will be rendered far more sensitive to current HER2 targeting drugs. 
 The general methodology: We have generated the first-of-its-kind cell model that shows the two distinct steps involved in the development of aggressive cancers by HER2. This has allowed us to compare the cells before and after the second step using powerful whole genome approaches, to begin to determine what the molecular mechanisms are that promote this second step in tumor progression. The preliminary data show that it is due to changes in metabolism, possibly due to acquired defects in the mitochondria, which are critical for cell metabolism. Our proposed methods involve more mechanistic studies of cell metabolism focusing on lipid metabolism, on the function of mitochondrial and the genetic and epigenetic mechanisms that may underlie this second step in tumor evolution. 
 Innovative elements of the project and potential impact: The discovery of this second step in the evolution of HER2 positive breast cancers is entirely novel and has never been reported before. Our goal is to understand the molecular mechanisms underlying this second step so that we can manipulate it using new types of drugs. Such drugs can potentially reverse the aggressive nature of such cancers, even at very advanced stages, or they may be used to prevent the progression of HER2 positive DCIS to invasive cancers. We can potentially even produce drugs that substantially increase the efficacy of HER2 inhibitors like lapatinib or neratinib, possibly putting patients with advanced HER2 positive breast cancer in complete remission, or hopefully even eradicate the disease at such advanced stages. The metabolic mechanisms underlying this second step in tumor evolution may even be present in HER2 negative breast cancers, such that the findings may be relevant to other subtypes of breast cancers.