Potential Kras G12C inhibitor.

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GrouseMan
Posts: 818
Joined: Mon Aug 12, 2013 12:30 pm
Location: SE Michigan USA

Potential Kras G12C inhibitor.

Postby GrouseMan » Tue May 28, 2019 7:16 pm

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
Last edited by GrouseMan on Tue May 28, 2019 7:19 pm, edited 1 time in total.
DW 53 dx Jun 2013
CT mets Liver Spleen lung. IVb CEA~110
Jul 2013 Sig Resct
8/13 FolFox,Avastin 12Tx mild sfx, Ongoing 5-FU Avastin every 3 wks.
CEA: good marker
7/7/14 CT Can't see the spleen Mets.
8/16/15 CEA Up, CT new abdominal mets. Iri, 5-FU, Avastin every 2 wks.
1/16 Iri, Erbitux and likely Avastin (Trial) CEA going >.
1/17 CEA up again dropped from Trial, Mets growth 4-6 mm in abdomen
5/2/17 Failed second trial, Hospitalized 15 days 5/11. Home Hospice 5/26, at peace 6/4/2017

hopefulandstrong
Posts: 42
Joined: Fri Apr 19, 2019 7:11 pm

Re: Potential Kras G12C inhibitor.

Postby hopefulandstrong » Tue May 28, 2019 7:18 pm

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!
54, female
1/8/19 DS Stage 4 with Liver Mets
1/11/19 Successful Colon Resect -- 12 inches of transverse colon removed
2/9/19 PET scan with disease confined to liver
2/18/19 Started Folfox -- CEA 70
5/1/19 -- Scans show progression -Switch to Folfiri
5/8/19 - BRAF mutation -- switch again to Triplet Therapy: Encorafenib, Binimetinib, Cetximab
6/13/19 - CEA dropped from 214 to 22
7/16/19 - CEA 2.8
8/1/19 - CT scan reveals 4 liver mets shrunk -- all under 3.1 CM.

Claudine
Posts: 120
Joined: Tue Mar 12, 2019 2:41 pm
Location: Montana

Re: Potential Kras G12C inhibitor.

Postby Claudine » Wed May 29, 2019 10:28 am

Thanks Grouseman, my husband is KRas G12D mutated so it's wonderful to read that there's research into targeting this mutation!
Wife of Dx 04/2018 (51 yo). MSS, KRAS mutated G12A
No primary, lytic tumor L4 vertebrae, CEA 10
Radiation 04/2018
Resection small intestine 05/18 (no cancer found - Krohn's disease)
Xelox * 6, 05/2018 to 10/2018
6.7 cm left adrenal mass 03/14/2019, 4.4 cm 05/21, 4.1 cm 09/16
SBRT L4 02/2019
Folfiri + Avastin
CEA since 03/15: 58, 17, 10, 6.4, 5, 4.8, 4.2, 3.6, 3.2, 3.3, 3.2, 3.7, 4.3, 4.2, 4.2,
Scan 03/14: Multiple small lung nodules
Scan 05/21: shrinking
Scan 09/16: lungs show no abnormalities (YAY!!!)

Brearmstrong
Posts: 85
Joined: Sun Mar 26, 2017 3:24 pm
Location: CT

Re: Potential Kras G12C inhibitor.

Postby Brearmstrong » Wed May 29, 2019 11:52 am

Promising news! Thanks for sharing. I'm KRAS G12D so will be watching this closely.
45 F Jan 17 2 sons
tumor appendix/colon
Muc Adeno 4cm
mod diff G2 T4aN2
nodes 8/50
CEA 4.6 after surgery <.05
KRAS G12D MSS
FOLFOX Apr-sep 17
Clean CT Jul 2017 lung 4mm, clean CT oct 17, CEA 3.4, nov 17 8.1. May 18 2.3,1.0,1.3, 1.3, 1.0, 2.3, 2.2, 2.1,2.2
Oct 2017 clean CT
Nov 17 PET para aortic nodes Stage IV
Folfori w/avastin Dec 17 CEA 7.1
May 18- surgery to remove nodes- 5 positive xeloda continues
Aug 18-CT NED Clear CT's Nov 18, Feb 19, May 19, Aug 19

User avatar
LPL
Posts: 650
Joined: Fri Apr 22, 2016 12:49 am
Location: Europe

Re: Potential Kras G12C inhibitor.

Postby LPL » Wed May 29, 2019 1:43 pm

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)..
DH @ 65 DX 4/11/16 CC recto-sigmoid junction
Adenocarcenoma pt 35x15x9mm G3(biopsi) G1(surgical)
Mets 3 Liver resectable
T4aN1bM1a Stage IVa 2/9 LN
MSS, KRAS-mut G13D
CEA & CA19-9: 5/18 2.5 78 8/17 1.4 48 2/14/17 1.8 29
4 Folfox 6/15-7/30 (b4 liver surgery) 8 after
CT: 8/8 no change 3/27/17 NED->Jan-19 mets to lung
:!: Steroid induced hyperglycemia dx after 3chemo
Surgeries 2016: 3/18 Emergency colostomy
5/23 Primary+gallbl+stoma reversal+port 9/1 Liver mets
RFA 2019: Feb lung met

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GrouseMan
Posts: 818
Joined: Mon Aug 12, 2013 12:30 pm
Location: SE Michigan USA

Re: Potential Kras G12C inhibitor.

Postby GrouseMan » Thu May 30, 2019 9:18 am

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
DW 53 dx Jun 2013
CT mets Liver Spleen lung. IVb CEA~110
Jul 2013 Sig Resct
8/13 FolFox,Avastin 12Tx mild sfx, Ongoing 5-FU Avastin every 3 wks.
CEA: good marker
7/7/14 CT Can't see the spleen Mets.
8/16/15 CEA Up, CT new abdominal mets. Iri, 5-FU, Avastin every 2 wks.
1/16 Iri, Erbitux and likely Avastin (Trial) CEA going >.
1/17 CEA up again dropped from Trial, Mets growth 4-6 mm in abdomen
5/2/17 Failed second trial, Hospitalized 15 days 5/11. Home Hospice 5/26, at peace 6/4/2017

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juliej
Posts: 3048
Joined: Thu Aug 05, 2010 12:59 pm

Re: Potential Kras G12C inhibitor.

Postby juliej » Thu May 30, 2019 6:39 pm

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
Stage IVb, liver/lung mets 8/4/2010
Xelox+Avastin 8/18/10 to 10/21/2011
LAR, liver resec, HAI pump 11/2011
Adjuvant Irinotecan + FUDR
Double lung surgery + ileo reversal 2/2012
Adjuvant FUDR + Xeloda
VATS rt. lung 12/2012 - benign granuloma!
VATS left lung 11/2013
NED 11/22/13 to 9/23/2019, CEA<1

User avatar
LPL
Posts: 650
Joined: Fri Apr 22, 2016 12:49 am
Location: Europe

Re: Potential Kras G12C inhibitor.

Postby LPL » Fri May 31, 2019 12:10 pm

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.
DH @ 65 DX 4/11/16 CC recto-sigmoid junction
Adenocarcenoma pt 35x15x9mm G3(biopsi) G1(surgical)
Mets 3 Liver resectable
T4aN1bM1a Stage IVa 2/9 LN
MSS, KRAS-mut G13D
CEA & CA19-9: 5/18 2.5 78 8/17 1.4 48 2/14/17 1.8 29
4 Folfox 6/15-7/30 (b4 liver surgery) 8 after
CT: 8/8 no change 3/27/17 NED->Jan-19 mets to lung
:!: Steroid induced hyperglycemia dx after 3chemo
Surgeries 2016: 3/18 Emergency colostomy
5/23 Primary+gallbl+stoma reversal+port 9/1 Liver mets
RFA 2019: Feb lung met


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