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Fra-1: a safeguard protecting tumor cells from oncogenic stress

Subject Area Gastroenterology
Term from 2018 to 2022
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 409543862
 
Final Report Year 2022

Final Report Abstract

With a 5-year survival rate of only 10%, pancreatic cancer (PDAC) remains a cancer with the worst prognosis. The incidence and mortality of PDAC are increasing and the therapy remains unsatisfactory. Therefore, novel and active therapies are needed. A prerequisite for the development of improved therapies is a better understanding of the disease and the effects of therapies. PDAC is initiated and driven by the KRAS oncogene and this oncogene is mutated in approximately 90% of cases. Oncogenic KRAS is activating the canonical signaling pathway, which transmits the signal via the RAF-MEK-ERK kinases into the nucleus to change the gene expression serving the demands of cancer cells. Our work demonstrated that the AP1 transcription factor family member FRA1 is tightly connected to the canonical KRAS signaling pathway. We show that FRA1 is highly expressed in the more aggressive, therapyresistant basal-like subtype of the disease. We describe that FRA1 expression and activity of the MYC oncogene are connected to the same subtype of the disease. By a detailed analysis of the molecular FRA1 functions, we observed that FRA1 can mediate the growth induced by oncogenic KRAS, but this function is redundant and can be compensated in cancer cells. Using unbiased drug screening experiments, we detected that FRA1 transfers resistance to inhibitors of the canonical RAF-MEK-ERK pathway. Consistently, mimicking a potent FRA1 inhibitor in a novel model system, in which tagged FRA1 degradation can be induced by a drug, we observed that inhibition of FRA1 exposes a dependency on the canonical KRAS signaling pathway. Mechanistically, we can demonstrate the activity of oncogenic KRAS signaling is controlled by FRA1, explaining the observed circuit. Our findings underscore the complex multi-layered buffering of oncogenic signaling in PDAC, where the loss of one signaling node is quickly compensated by the upregulation of another node. These rapid adaptations make mono-targeted therapies challenging and point to the need to decipher in more detail the molecular mechanisms. Pharmacological FRA1 inhibition, which we mimic in our model systems, renders PDAC cells sensitive to RAF-, MEK-, ERK-inhibition. Inhibitors of the kinases are already approved for the therapy of different solid tumors in the clinic but failed so far in PDAC clinical trials. Therefore, our work provides a rationale to develop FRA1 inhibitors and offers opportunities for the development of mechanism-based combination therapies.

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