FOSL1 Fuels Cancer?

KRAS mutations are responsible for a large number of human cancers – but why? Clearly, more insight into the mechanisms involved could deepen our understanding of certain cancers, as well as offer up new diagnostic and therapeutic possibilities. Silve Vicent co-led a team of researchers who saw the opportunity to delve deeper into the mechanisms of KRAS-mutated tumors – and their findings showed that transcription factor FOSL1 is highly expressed in lung and pancreatic cancer patients (1), implicating the protein as a possible diagnostic biomarker. To further unzip what information the gene may hold, we spoke with Vicent, assistant professor at the University of Navarra’s Center for Applied Medical Research.

What was your goal during the investigation?

We aimed to expose common core elements of KRAS oncogene signaling relevant for the homeostasis of KRAS-mutated tumors. To do this, we followed a two-tiered “zoom-in” strategy. The first part involved identifying KRAS-regulated genes by a cross-species meta-analysis of laboratory data, and the second included selecting genes frequently upregulated across human KRAS-driven cancers. We did this by contrasting the cross-species signature against a panel of five different tumor types where KRAS is frequently mutated. We chose FOSL1 for follow-up experiments because it was the only gene whose high expression was a marker of poor survival in KRAS-related lung and pancreatic cancer patients.

How did you further elucidate the protein’s role?

To follow up on the role of FOSL1 in those cancers, we carried out in vitro and in vivo studies of human and mouse cancer cell line panels, where FOSL1 was inhibited via RNAi. We investigated the characterization of FOSL1 expression levels in patient-derived xenografts, the genetic abrogation of FOSL1 in genetically engineered mouse models, and the pharmacological inhibition of FOSL1 targets in combination with KRAS inhibition (using inhibitors that are under investigation in clinical trials).

Could FOSL1 could play a role in non-KRAS cancers?

We have shown that FOSL1 expression can be regulated through several kinase modules downstream of the KRAS oncogene. It is likely that non-KRAS genetic alterations may trigger activation of such kinase modules to upregulate FOSL1 expression in other tumors. For example, you can find genetic alterations that increase FOSL1 expression in the Wnt pathway in colon cancer, and in the NF1 gene in gliomas and glioblastomas.

What’s next?

At this stage, we are focusing on two main goals. First, we are working to discern which FOSL1 transcriptional targets mediate its deleterious effects in KRAS-mutated tumors. Second, we are looking for inhibitory strategies that target KRAS-mutated tumors – involving depletion of FOSL1 in conjunction with chemotherapy and/or targeted therapies currently in the clinic.

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References

1. A Vallejo et al., “An integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer”, Nat Commun, 8, (2017). PMID: 28220783.

About the Author(s)

William Aryitey

My fascination with science, gaming, and writing led to my studying biology at university, while simultaneously working as an online games journalist. After university, I travelled across Europe, working on a novel and developing a game, before finding my way to Texere. As Associate Editor, I’m evolving my loves of science and writing, while continuing to pursue my passion for gaming and creative writing in a personal capacity.

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