Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

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.”



ResearchBlogging.orgLing, 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

4 Responses to “On KRAS, NF-kB activation and pancreatic cancer”

  1. Mark Fortner

    OK.  You’ve piqued my curiosity.  Why is KRAS such an intractable target?  Which trials have failed so far and why? 

    • maverickny

      Here’s a good overview on RAS mutations in cancers, Mark:  

      RAS mutations are both oncogenic and also highly dependent on autophagy to ensure their survival – most TKIs actually increase autophagy since they are protein based, so with RAS mutations we may be feeding the tumour indirectly rather than suppressing it.

      There are more failed trials than I can list here, but they include sorafenib for one.  We also know that colon cancers that are mutated rather than wild type cause resistance to EGFR inhibitors such as Erbitux and Vectibix, for example.  Melanomas with NRAS mutations are particularly difficult to treat, for example, and most of those patients do poorly on any therapeutic.

      • Mark Fortner

        Thanks, Sally.  I’ll take a look at the link you sent me.  Here’s why I was interested:
        It seems in their mouse model they were able to induce a KRAS-G12D mutation, and reverse it, and in the process reverse precursor lesions and fully-developed tumors.  You can read the paper for more details.

        I looked at DrugBank for any drugs that specifically target KRAS and didn’t find anything (although I’m not sure they list INDs there).  Does the FDA have a site where INDs (and their targets) are listed?

        I also looked at and found a number of trials, but they seemed to be for downstream targets like MEK (more in line with your comment and your posting).

        • maverickny

          I remember seeing that paper; it’s very interesting indeed, but the challenge is going from mice to man… we also need to see what happens in xenograft and human models. A post specifically on KRAS mutations is on my long list of posts to do – great lecture at the NYAS last week that mentioned KRAS G12D in colon and lung reminded me that I need to finish the research on this area first.  Thanks for the nudge, Mark!

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