WAKE UP AND SMELL THE COFFEE. THE STORY OF DDR2
ONE OF THE MOST POWERFUL PAPERS
Yes--you read that right!
The journal
Cancer Discovery reports in a publish ahead-of-print
article (abstract) the discovery of mutations in the
discoidin domain receptor 2 tyrosine kinase (
DDR2)
gene in a series of lung squamous cell carcinomas (SQC) that may
identify a potential therapeutic target similar to those described for
lung adenocarcinomas. Interestingly, DDR2 is a receptor kinase that
normally binds collagen as its ligand and has been shown to promote cell
migration, proliferation, and survival when activated by ligand binding
and phosphorylation.
While subtypes of lung adenocarcinoma (ADC) have been increasingly
better defined and characterized on multiple levels with respect to
identifying therapeutic targets/responses, minimal progress has been
made with squamous cell carcinoma.
The authors of this study used conventional Sanger sequencing of 201
genes, including the entire tyrosine kinome, in an initial set of 20
primary lung SQC and matched normal controls and identified 2 samples
with DDR2 mutations; a secondary screen of 48 lung SQC samples
identified an additional 4 DDR2 mutations. Following this, the authors
sequenced DDR2 in a validation cohort of 222 primary lung SQC samples
and identified 5 additional samples with mutations. Excluding samples
from lung SQC cell lines, there was an overall frequency of 3.2% of DDR2
mutations in primary lung SQC samples--
about the same frequency reported for ALK fusion mutations in lung ADC.
The authors analyzed the TKIs imatinib and dasatinib, previously reported to inhibit DDR2, to evaluate whether targeting
DDR2 mutated in SQC might be a potential therapeutic strategy.
Dasatinib showed particular efficacy in inhibiting proliferation and promoting cell death through apoptosis in SQC cell ines with
DDR2 mutations.
In addition, they report one of 7 subjects from an early-phase trial of
dasatinib or combination dasatinib and erlotinib with advanced stage
lung SQC cancer who exhibited significant shrinkage in tumor size while
receiving the dasatinib/erlotinib combination. The authors were able to
perform direct sequencing of DDR2 in a pretreatment tumor specimen from
this individual and identified a novel
DDR2 kinase mutation.
This is an intriguing paper that you might well keep in mind.
Hopefully, this may stimulate other investigators to not only look for
other potential genomic alterations that either drive SQC and/or
represent targetable proteins but also go back and scrutinize
histological and other clinicopathological characteristics of lung SQC
that may have therapeutic or prognostic importance.
ONE OF THE MOST POWERFUL TREATMENT AGAINST A DISEASE IS TO FIND THE TARGET THAT INITIATED IT. THE STRONGEST EVIDENCE THAT A TARGET MOLECULE IS A CRITICAL MOLECULE IS WHEN ITS MUTATION SHORTENS A LIMB IN INDIVIDUALS AND DDR2 MUTATION DOES EXACTLY THAT !!!!
It reminds me of the story of Thalidomide. And the 2 can be linked. I am only 50% of this! And whenever a limb is missing, your Angiogenesis and Differentiation are not very far and sure enough, Dasatinib, Imitanib and most likely Thalidomid are not far, lurking in the neighborhood!
SPONDYLO META EPIPHYSEAL DYSPLASIA (SMED) IS THE CONDITION OF SHORT STATURE AND SMALL LIMBS THAT IS RELATED TO DDR2 MUTATION!
SCIENTISTS DID NOT SLEEP, THEY LOOKED IN LUNG CANCER WHAT DASATINIB WOULD DO IN THESE PATIENTS WITH DDR2 MUTATION AND SURE ENOUGH, DASATINIB WORKS. The proof of concept is there in the pudding.
Now don't go out hunting for any short stature individual to test their gene. But nature has given us a clue that all short stature gene found in a cancer cell, should not only tell us that the gene is targetable by an anti-VEGF and related kinase. WE SHOULD BE TESTING ALL CANCER FOR DDR2, AND TREAT WITH DASATINIB. CURE IN THOSE CASES IS REACHABLE! And may be we can prevent all stature with these drug. One thing for sure, let's find DDR 2 in triple negative breast cancer, and we know what to give pronto now!
