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Autophagy and cell fate in K-Ras mutant lung cancer cells

Institution: University of California, San Francisco
Investigator(s): Jayanta Debnath, M.D.
Award Cycle: 2009 (Cycle 18) Grant #: 18XT-0106 Award: $250,000
Subject Area: Cancer
Award Type: Exploratory/Developmental Award

Initial Award Abstract
Lung cancer is the leading cause of cancer death, both in the United States and worldwide. Unfortunately, this disease is largely preventable because the majority of cases are attributable to smoking. Nonetheless, because of the extensive lethality currently associated with smoking-related lung cancers, we urgently require new therapeutic approaches to treat smokers who develop these tumors. About 85% of all lung cancers are a type of tumor called non-small cell lung carcinoma (NSCLC). Importantly, the most common abnormality found in NSCLC involves a molecule called KRas. Extensive research indicates that chemicals in cigarette smoke commonly cause specific mutations in the KRAS gene, turning it into a cancer-promoting molecule (called an oncogene). In fact, KRas mutations, which are present in up to 20% of all patients with NSCLC, are almost exclusively found in smokers.

Most importantly, smokers who develop lung cancer with KRas mutations invariably have a very bad prognosis, because they do not respond to standard chemotherapy or to targeted therapies more beneficial for non-smokers with lung cancer. Thus, new processes and pathways capable of killing or suppressing the growth of lung cancer cells with KRas mutations must be identified; such discoveries will potentially benefit a large number of large patients with these common and lethal smoking-related abnormalities in KRas.

We believe that we have identified a cellular process, called autophagy, which can be used to precisely target KRas mutant lung cancer cells. During autophagy, a cell digests and recycles its own contents (i.e., literally “eats itself”), which provides cancer cells with the resources and energy they need to effectively to respond to acute stress—during starvation or even chemotherapy, for instance. Our preliminary work indicates that cancer cells expressing mutated KRas exhibit very high levels of autophagy. We hypothesize that the increased autophagy in KRas mutant cells contributes to their well-being, and to the detriment of the patient. In support of this model, when we inhibit autophagy in mutant KRas-expressing cells, they no longer behave like cancer cells; indeed, they completely lack the ability to grow and survive in adverse conditions. Based on this data, we believe that autophagy inhibition can be exploited to kill or suppress the growth of lung cancer cells with smoking-related KRas mutations. Through this TRDRP Exploratory Award proposal, we will obtain the preliminary data to prove this novel concept. Our proposed studies will lay the foundation for future work to translate these findings and manipulate autophagy to treat the large number of smokers who develop lung cancers with invariably lethal KRas mutations.