Pharma Strategy Blog

Over the last couple of days we have looked at targeted therapies designed to inhibit some of the molecular peculiarities associated with non-squamous lung cancer, and adenocarcinomas in particular.

Squamous Cell Lung Cancer

As far as I know, there are no approved targeted therapies specifically for squamous cell carcinoma (SCC) of the lung, so chemotherapy is very much the standard of care still, although response rates tend to be disappointing.  Unlike adenocarcinomas, this subset is more often associated with smoking.  It also represents a large group of approximately 25% of NSCLC.

Previously, we have discussed FGFR1 mutations in SCC as a potential target, but although there a several FGFR inhibitors in the clinic, I couldn’t find any specifically being tested in SCC lung cancer.

Recently though, Peter Hammerman and Matthew Myerson (Dana Farber) published interesting data at the annual AACR meeting identifying a potential new therapeutic target, discodin domain receptor 2 (DDR2), in squamous cell carcinoma of the lung.

What does this new research on DDR2 tell us?

Cancer Discovery from AACR

I’ve been meaning to write about this exciting development since the AACR meeting, but the data was published in the new journal Cancer Discovery.

Somewhat perversely, the DOI references are not yet showing up in PubMed or Research Blogging, so I finally resorted to adding the reference manually.

If the link in the Reference section at the end of the blog post doesn’t work, you can download the article (open access PDF) below:

Mutations in the DDR2 Kinase Gene identify a Novel therapeutic target in squamous cell lung cancer

Essentially, Sanger sequencing was employed to look at the tyrosine kinome and determine whether any relevant mutations existed in 290 SCC samples.  The schema for the Hammerman et al’s (2011) research is described below:

DDR2 is a receptor kinase that binds collagen as its exogenous ligand and has previously been shown to promote cell migration, proliferation and survival when activated.

Ultimately, DDR2 mutations were observed in 11 of the 290 samples in the validation screen.  The researchers observed that these DDR2 mutations occurred in 3.8% of lung squamous cell carcinomas, and in xenograft models these appeared to show a sensitivity to dasatinib (Sprycel), a multi-kinase inhibitor approved for the treatment of Ph+ chronic myeloid leukemia (CML).

Several kinase inhibitors were evaluated, including imatinib, but dasatinib was found to be particularly sensitive.  The reason is that has a much lower fluorescent resonance energy transfer (FRET) measurement (5.4 nM) than imatinib (71.6 nM) for recombinant DDR2.  Interestingly, both nilotinib (35.4 nM) and ponatinib (5.4 nM) also showed activity in SCC cell lines harbouring DDR2, although ponatinib appeared to be the more potent of the two, with activity in line with dasatinib in this setting.

Subsequently, it was observed that a SCC lung patient with a DDR2 mutation responded well to a combination of dasatinib and erlotinib therapy, suggesting a clinical trial might be in order to determine efficacy and also safety on a broader scale, since dasatinib is associated with adverse events such as pleural and pericardial effusions in CML, possibly from off-kinase Src activity.

For those interested, you can listen to a short podcast via Cancer Discovery with Matthew Myerson on the DDR2 mutation.

Conclusions

Overall, the landscape in lung cancer is rapidly changing as more molecular targets are being identified, along with therapies that specifically inhibit the driving cancerous activity.

EGFR mutations were the first major breakthrough in targeted therapies, but with the discovery of ALK translocations, T790M mutations (all adenocarcinomas) and now with FGFR1 and DDR2 (squamous), we have exciting opportunities to potentially match therapies to patients in non-small cell lung cancer in a new era of molecularly targeted and personalised therapy, assuming clinical trials corroborate the promise of the targets, that is.

I can see a time in the not too distant future that we will start diagnosing, testing and treating people with lung cancer based on their molecular abnormalities on a more routine basis with targeted therapies, rather than merely test for histology, which is a rather crude and heterogeneous way of looking at the conundrum.  Of course, we would still need to research and tackle the adaptive resistance pathways that emerge, but it would certainly be a huge improvement on toxic chemotherapies we have now… and that would be a major step forward for this devastating disease.

Check back tomorrow for the next article in the series on lung cancer targets!

References:

Peter S. Hammerman, Martin L. Sos, Alex H. Ramos, Chunxiao Xu, Amit Dutt, Wenjun Zhou, Lear E. Brace, Brittany A. Woods, Wenchu Lin, Jianming Zhang, Elisabeth Brambilla, Christian Brambilla, Philippe Lorimier, Odd Terje Brustugun, Åslaug Helland, Iver Petersen, Joachim H. Clement, Harry Groen, Wim Timens, Hannie Sietsma, Erich Stoelben, Jürgen Wolf, David G. Beer, Ming Sound Tsao, Megan Hanna, Charles Hatton, Michael J. Eck, Pasi A. Janne, Bruce E. Johnson, Wendy Winckler, Heidi Greulich, Adam J. Bass, Jeonghee Cho, Daniel Rauh, Nathanael S. Gray, Kwok-Kin Wong, Eric B. Haura, Roman K. Thomas, & Matthew Meyerson (2011). Mutations in the DDR2 Kinase Gene identify a Novel therapeutic target in squamous cell lung cancer Cancer Discovery, 1 (1), 78-89 : 10.1158/2159-8274.CD-11-0005