Potential Kras G12C inhibitor.

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GrouseMan
Posts: 888
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: 58
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; Successful Colon Resect
2/18/19 Started Folfox -- CEA 70
5/8/19 - BRAF mutation -- switch to Triplet Therapy: Encorafenib, Binimetinib, Cetximab
6/13/19 - CEA dropped from 214 to 22
8/29 - CEA jump to 30-- scans reveal liver spread, though still confined. triplet therapy abandoned; some concern about PIC3 mutation interfering with BRAF treatment
9/1 - 10/4 -- no treatment
10/4 -- folfoxfiri to stem further progression; pump placement in January (hopefully)

claudine
Posts: 809
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 04/18 (51 yo). MSS, KRAS G12A, no primary

Tumors: L4 04/18; left adrenal gland & small lung nodules 03/19
rectum 02/22 (pT3 pN0 stage 2A); L3 09/22

Surgeries: intestinal resect. 05/18 (no cancer - Crohn's); adrenalectomy 02/20
L3-L4-L5 fusion and corpectomy 05/20; LAR 04/22; ileo reversal 09/22
L2-L3 fusion and corpectomy 09/22

Treatments: EBRT 04/18; SBRT 02/19; Failed adjuvant Xelox ; Folfiri/Avastin 03/19 - 01/20
adjuvant chemorad (Xeloda) 06/22; SBRT 11/22; Xeloda/Avastin since 01/24

Brearmstrong
Posts: 112
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.
50 F diag 1/17
Muc Adeno 4cm
mod diff G2 T4aN2
nodes 8/50
CEA 4.6 after surgery <.05
KRAS G12D MSS
FOLFOX Apr-sep 17
Nov 17 PET p aortic nodes Stage IV
Folfori w/avastin
May 18 surgery on nodes xeloda 2yr
Aug 18-May 20 NED
July 20 hysterectomy
July 21 vats right lung
Clinical trial- failed liver Mets biopsy shows now poorly differentiated carcinoma.
HAI pump at MSK may 2022
Nov met to pancreas- causing pain
Radiation ablation to pancreas Dec 22
New lung Mets watch and wait

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LPL
Posts: 651
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 35x15x9mm G3(biopsi) G1(surgical)
Mets 3 Liver resectable
T4aN1bM1a 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 NED again Oct-19 :)
:!: 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 & Oct lung mets

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GrouseMan
Posts: 888
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: 3114
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 12/18/2019, CEA<1

User avatar
LPL
Posts: 651
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 35x15x9mm G3(biopsi) G1(surgical)
Mets 3 Liver resectable
T4aN1bM1a 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 NED again Oct-19 :)
:!: 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 & Oct lung mets


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