The Colon Club

The Kras G12C mutation occurs in about 7.9 % of colon Cancer patients tumors. So granted this isn't perhaps a great therapeutic discovery for colon cancer. However it seems that a good (150nM IC50) inhibitor - ARS-1620 is an atropisomeric one selective for KRASG12C a mutant form of the guanosine triphosphatase (GTPase) KRAS. Seems it may have some synergy with EGFr FGFr and other inhibitors.

See: https://stke.sciencemag.org/content/12/ ... id=2836996

From the abstract I think this was probably a cellular assay and not a mouse or clinical model at this time but it seems to indicate that at least this mutation could be targeted with ARS-1620 and an EGFr Inhibitor or FGFR inhibitor to overcome the tendency of KRAS Mutations not being sensitive to these reagents. The study was done with Pancreatic and Lung Cancer cell lines mostly. Also note this targets only the mutant form which is good such that it doesn't effect the wild type and may be much less prone to systemic side effects on normal tissues!

Other work I have recently read about seems to indicate a similar small molecule synthesis approach to creating inhibitors for KRas G12D which is much more prevalent in Colon Cancers (34%) might also be able to follow a similar type of Therapeutic method as developed for this G12C mutation.

Regards,

GrouseMan

As BRAF person, I gotta say, these discoveries are downright thrilling. The idea that they can get that detailed about what is/isn't going on, and attack it with increasing precision. Rock On!

Thanks Grouseman, my husband is KRas G12D mutated so it's wonderful to read that there's research into targeting this mutation!

Promising news! Thanks for sharing. I'm KRAS G12D so will be watching this closely.

GrouseMan wrote:The Kras G12C mutation occurs in about 7.9 % of colon Cancer patients tumors. So granted this isn't perhaps a great therapeutic discovery for colon cancer. However it seems that a good (150nM IC50) inhibitor - ARS-1620 is an atropisomeric one selective for KRASG12C a mutant form of the guanosine triphosphatase (GTPase) KRAS. Seems it may have some synergy with EGFr FGFr and other inhibitors.

See: https://stke.sciencemag.org/content/12/ ... id=2836996

From the abstract I think this was probably a cellular assay and not a mouse or clinical model at this time but it seems to indicate that at least this mutation could be targeted with ARS-1620 and an EGFr Inhibitor or FGFR inhibitor to overcome the tendency of KRAS Mutations not being sensitive to these reagents. The study was done with Pancreatic and Lung Cancer cell lines mostly. Also note this targets only the mutant form which is good such that it doesn't effect the wild type and may be much less prone to systemic side effects on normal tissues!

Other work I have recently read about seems to indicate a similar small molecule synthesis approach to creating inhibitors for KRas G12D which is much more prevalent in Colon Cancers (34%) might also be able to follow a similar type of Therapeutic method as developed for this G12C mutation.

Regards,

GrouseMan

GrouseMan, have you seen any new research about KRAS G13D?
It is very positive this about G12C !! Hoping the KRAS research will expand to the others that don’t have the “C” (Cysteine)..

LPL - I have probably mentioned this before but people with KRAS G13D mutations are often relegated to the NO EGFr inhibitor treatment group along with all the other KRAS mutations. This is a biased position by many oncologist in that they can't wrap their head around the fact that G13D patients do respond to these Anti EGFr drugs. There has been a some incidental evidence of this for some time. The most recent paper coming from a VERY reliable source (Salk and Scripts Institutes) does a systems biology analysis along with conformational cellular studies to show that yes tumors with KRAS G13D mutations will respond favorably to Cetuximab treatment (and probably other anti EGFr treatments including MEK inhibitors)

See: https://www.biorxiv.org/content/biorxiv ... 1.full.pdf
and from 2015: https://www.researchgate.net/publicatio ... e_survival

I see from your signature you have never had a treatment that includes an EGFr inhibitor. Maybe you should try to inform your Oncologist of this research.

Regards,

GrouseMan

GrouseMan wrote:I have probably mentioned this before but people with KRAS G13D mutations are often relegated to the NO EGFr inhibitor treatment group along with all the other KRAS mutations. This is a biased position by many oncologist in that they can't wrap their head around the fact that G13D patients do respond to these Anti EGFr drugs. There has been a some incidental evidence of this for some time. The most recent paper coming from a VERY reliable source (Salk and Scripts Institutes) does a systems biology analysis along with conformational cellular studies to show that yes tumors with KRAS G13D mutations will respond favorably to Cetuximab treatment (and probably other anti EGFr treatments including MEK inhibitors)

See: https://www.biorxiv.org/content/biorxiv ... 1.full.pdf
and from 2015: https://www.researchgate.net/publicatio ... e_survival

Thanks, GrouseMan, for these links!!!

It's insane that so many oncologists take this clearly non-evidence-based position. Hopefully, the articles you mentioned can be used by KRAS G13D patients to support the use of anti-EGFR drugs in their treatment.

Juliej

GrouseMan wrote:LPL - I have probably mentioned this before but people with KRAS G13D mutations are often relegated to the NO EGFr inhibitor treatment group along with all the other KRAS mutations. This is a biased position by many oncologist in that they can't wrap their head around the fact that G13D patients do respond to these Anti EGFr drugs. There has been a some incidental evidence of this for some time. The most recent paper coming from a VERY reliable source (Salk and Scripts Institutes) does a systems biology analysis along with conformational cellular studies to show that yes tumors with KRAS G13D mutations will respond favorably to Cetuximab treatment (and probably other anti EGFr treatments including MEK inhibitors)

See: https://www.biorxiv.org/content/biorxiv ... 1.full.pdf
and from 2015: https://www.researchgate.net/publicatio ... e_survival

I see from your signature you have never had a treatment that includes an EGFr inhibitor. Maybe you should try to inform your Oncologist of this research.

Regards,

GrouseMan

Thank You GrouseMan !
That first (most recent) paper is so good - such a thorough investigation to find explanation to why KRAS G13D can behave different. Very interesting!!! I hope this paper will be read by the audience it deserves.
And Yes I’m glad I know about it in case my husband should need more chemo.