Pharma Strategy Blog

Pancreatic cancer as many readers know, is one of those cancers that is generally diagnosed later than most in stage IV and as a result, has a poor prognosis, often only a year or so from diagnosis.

It has been known for a decade that constitutive Kras and NF-kB activation is one of the signature changes in the disease in the majority (80-95% ) of patients. Kras is a particularly important gene because it is often involved with on-off signaling of other genes. In addition, mutational inactivation of a key tumour suppressor gene (Ink4a/Arf) also occurs in over half (50-75%) of pancreatic adenocarcinomas. What is not known, however, is what are the key signaling pathways downstream of Kras and how they relate to pancreatic cancer.

Earlier this month though, Ling et al., (2012) published some new data in Cancer Cell advancing our knowledge in this area:

“Our findings reveal that KrasG12D-activated AP-1 induces IL-1a, which, in turn, activates NF-kB and its target genes IL-1a and p62, to initiate IL-1a/p62 feedforward loops for inducing and sustaining NF-kB activity.”

They also noted the impact of this process, namely:

“IL-1a overexpression correlates with Kras mutation, NF-kB activity, and poor survival in PDAC patients.”

In other words, dual feedforward loops of IL-1a (induced by AP-1) and p62 are responsible for the IKK2/b/NF-kB activation by KrasG12D.

The group also observed:

“Our results show that TSC1 and FOXO3a pathways are involved in Kras-induced PDAC.”

In other words, they promote tumorigenesis.

What does this data mean?

In practice, this research suggests that several approaches might be potentially useful:

• Inhibiting mutated Kras (specifically KrasG12D) may be a viable therapeutic target in pancreatic cancer.
• Since IL-1a overexpression correlates with poor survival in PDAC patients, pharmacologic targeting of IL-1a may also be a useful strategy to consider.

Kras mutations appear in a number of cancers, including pancreatic and colon cancers, where in the latter case, they have been shown to cause resistance to EGFR inhibitors.  To date, strategies to target Kras have been disappointing at best.  There are also a number of MEK and other inhibitors being evaluated in pancreatic and other cancers, but I’m not sure that targeting downstream of RAS will have any effect in these cases, if mutated RAS upstream is the main issue:

Source: ReactionBiology

MD Anderson summed up this data in pancreatic adenocarcinoma nicely in a succinct press release describing the feedforward loops as a ‘vicious circle’ i.e.:

“A self-perpetuating loop of molecular activity that fuels pancreatic cancer by promoting inflammation, development of new blood vessels and blocking programmed cell death.”

 

References:

Ling, J., Kang, Y., Zhao, R., Xia, Q., Lee, D., Chang, Z., Li, J., Peng, B., Fleming, J., Wang, H., Liu, J., Lemischka, I., Hung, M., & Chiao, P. (2012). KrasG12D-Induced IKK2/β/NF-κB Activation by IL-1α and p62 Feedforward Loops Is Required for Development of Pancreatic Ductal Adenocarcinoma Cancer Cell, 21 (1), 105-120 DOI: 10.1016/j.ccr.2011.12.006