Zie ook dit artikel: https://kanker-actueel.nl/vaccin-tegen-kras-positief-gemuteerde-vormen-van-kanker-darmkankers-en-longkanker-oa-wordt-gecombineerd-met-trametinib-een-anti-pd-medicijn-in-fase-i-studie-na-hoopvolle-resultaten.html

14 april 2022: Bron: 2022 Apr 1;12(4):924-937. Met dank aan Ton die me deze reviewstudie stuurde.

Uit een reviewstudie blijkt dat wanneer KRAS positieve tumoren, zoals die vaak voorkomen bij darmkanker, alvleesklierkanker en longkanker maar in feite bij veel meer vormen van kanker met solide tumoreen voorkomt, behandeld worden met een combinatie van verschillende medicijnen de resultaten sterk verbeteren. De titel van de reviewstudie zegt het eigenlijk al:  "Het bereik van precisie-oncologie vergroten door alle KRAS mutaties te drogeren. 

Interessant is ook een artikel op de website van het AvL - Amsterdam over dit onderwerp: 

Hyperactief kanker-eiwit blijkt onverwacht toch in te dammen

28 mei 2018 14:46

Dertig procent van alle gevallen van kanker ontstaat door een fout in het KRAS-gen, waardoor de celdeling ontspoort. Kanker die veroorzaakt wordt door deze mutatie is slecht te behandelen, een voorbeeld is alvleesklierkanker. Onderzoekers van het Antoni van Leeuwenhoek stuitten nu, onder leiding van Rene Bernards, onverwacht op een aanknopingspunt om kanker met deze mutatie in de toekomst mogelijk te kunnen behandelen met een doelgericht medicijn.



Hier een overzicht van de medicijnen onderverdeeld in verschillende groepen van medicijnen die in studies worden onderzocht om KRAS positieve tumoren aan te pakken. 

Mutant-specific KRAS inhibitors, pan-(K)RAS inhibitors, SHP2 inhibitors, and SOS1 inhibitors described in ClinicalTrials.gov or currently in advanced preclinical stages

Een stukje uit de introductie vertaald:

In 2020 waren er wereldwijd naar schatting 19,3 miljoen nieuwe gevallen van kanker, waarvan 1,8 miljoen nieuwe gevallen alleen al in de Verenigde Staten (zie ref. 1, 2). Recente analyses hebben aangetoond dat ongeveer een op de zeven van alle menselijke kankers KRAS-veranderingen (Kirsten-ratsarcoomvirus) bevat, waardoor het een van de belangrijkste oncogene oorzaken van kanker bij de mens is (zie ref. 3–5). Het KRAS-eiwit is een klein membraangebonden GTPase (GTP-hydrolase), dat fungeert als een schakelaar voor een groot aantal cellulaire signaalfuncties (zie Fig. 1A).

Tekst gaat onder afbeelding door. 

Figure 1. Overview of the RAS/MAPK signaling pathway and patient numbers/overall cohort prevalence for distinct KRAS alleles/amplification in seven cancer types. A, Schematic representation of KRAS cycling and signaling highlighting selected drug targets and inhibitors. B, Distribution of KRAS alleles/amplification and patient numbers in selected tumor types. Mutation and amplification rates for KRAS have been derived from the AACR GENIE 9.0 public database, whereas patient numbers for the respective tumor types have been extracted from the Cancer Facts & Figures 2000 report published by the American Cancer Society (2). The number of cases for lung adenocarcinoma was set to 40% of all lung cancers. In total, 81,996 distinct samples with mutation and copy number profiles were collapsed into unique patient samples and filtered for distinct alleles and amplification of KRAS. The top seven alleles/amplifications with the highest overall prevalence across tumor types are shown, whereas other mutations are grouped into the class “Other.” The grouping “Multiple” contains all cases, for which different KRAS alterations have been observed in a single patient, for example, two different mutations or a mutation coupled with a KRAS amplification. The “Total” subpanel summarizes the patient numbers for the seven cancer types depicted and ranks the alterations based on overall numbers. Similarly, patient numbers are highlighted for each tumor type and each alteration. The percentages in parentheses reflect the proportion in relation to the full cohort (e.g., 13.6% of all patients with lung adenocarcinoma carry a KRASG12C mutation). AMP, amplification; CRC, colorectal cancer; EAC/GEJC, esophageal adenocarcinoma/gastroesophageal junction cancer; IDC, invasive ductal carcinoma; LUAD, lung adenocarcinoma; PDAC, pancreatic ductal adenocarcinoma; STAD, stomach adenocarcinoma; UEC, undifferentiated endometrial carcinoma.


Overzicht van de RAS/MAPK-signaleringsroute en patiëntaantallen/algemene cohortprevalentie voor verschillende KRAS-allelen/amplificatie bij zeven kankertypes.
A, Schematische weergave van KRAS-cycli en -signalering die geselecteerde medicijndoelen en remmers benadrukken. B, Verdeling van KRAS-allelen/amplificatie en patiëntaantallen in geselecteerde tumortypes.

Mutatie- en amplificatiesnelheden voor KRAS zijn afgeleid van de AACR GENIE 9.0 openbare database, terwijl patiëntnummers voor de respectieve tumortypes zijn geëxtraheerd uit het Cancer Facts & Figures 2000-rapport dat is gepubliceerd door de American Cancer Society (2). Het aantal gevallen voor longadenocarcinoom werd vastgesteld op 40% van alle longkankers. In totaal werden 81.996 verschillende monsters met mutatie- en kopienummerprofielen samengevouwen tot unieke patiëntmonsters en gefilterd op verschillende allelen en amplificatie van KRAS. De zeven beste allelen/amplificaties met de hoogste algemene prevalentie voor alle tumortypes worden weergegeven, terwijl andere mutaties zijn gegroepeerd in de klasse 'Overig'.
De groepering "Meerdere" bevat alle gevallen waarbij verschillende KRAS-veranderingen zijn waargenomen bij een enkele patiënt, bijvoorbeeld twee verschillende mutaties of een mutatie gekoppeld aan een KRAS-amplificatie.
Het subpaneel "Totaal" vat de patiëntaantallen voor de zeven afgebeelde kankertypes samen en rangschikt de wijzigingen op basis van totale aantallen. Evenzo worden patiëntnummers gemarkeerd voor elk tumortype en elke wijziging. De percentages tussen haakjes geven de verhouding weer ten opzichte van het volledige cohort (bijv. 13,6% van alle patiënten met longadenocarcinoom draagt ​​een KRASG12C-mutatie).


Recente onderzoeken met SHP2- en SOS1-remmers in door KRAS aangestuurde kankercellijnen, evenals biochemische onderzoeken van KRAS-mutanten in overigens RAS-loze muizenembryofibroblasten, hebben aangetoond dat een reeks KRAS-oncoproteïnen tussen hun actieve en inactieve toestand wisselen en afhankelijk blijven op nucleotide-uitwisseling voor activering (zie ref. 11-13).

Het richten op KRAS mutaties bij kanker is de afgelopen vier decennia een centraal doel geweest en de onderzoeks- en ontwikkelingsinspanningen zijn de afgelopen 10 jaar geïntensiveerd, grotendeels veroorzaakt door de baanbrekende ontdekking door J. Ostrem, K. Shokat en collega's (zie ref. 14) van verbindingen die zijn vastgebonden aan de cysteïne van KRASG12C. De recente versnelde goedkeuring van de KRASG12C-mutant-selectieve remmer sotorasib (AMG 510) voor de behandeling van patiënten met tweedelijns KRASG12C-mutatie positieve niet-kleincellige longkanker (NSCLC) door de FDA op 28 mei 2021, markeert de eerste goedgekeurde gerichte therapie voor tumoren met een KRAS-mutatie, Zie FDA goedkeuring.

Een tweede KRASG12C-remmer, adagrasib (MRTX849), heeft onlangs de status van doorbraaktherapie gekregen en acht aanvullende remmers zijn in klinische studies opgenomen. Ondanks het succes van KRASG12C-mutant-selectieve remmers voor G12C-aangedreven NSCLC's, ontbreekt het bij meer dan 85% van alle KRAS-gemuteerde kankers echter nog steeds aan effectieve therapieën.

De reikwijdte van deze review is om de onvervulde behoefte aan patiënten met KRAS-mutaties te benadrukken en het uitdagende doel om alle oncogene KRAS-varianten over mutatie- en kankertypen te drogeren. Deze beoordeling biedt ook een update en vooruitzichten op de meest veelbelovende therapeutische benaderingen voor het genereren van pan-KRAS-concepten die gericht zijn op het brengen van precisietherapie-opties voor een breed scala van KRAS-gestuurde kankers.


De reviewstudie beschrijft tot in detail nog veel meer hoe de stand van zaken is betreffende KRAS mutaties, en kunt u lezen in de reviewstudie, klik op de titel:

Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants 

Crossmark: Check for Updates
Cancer Discov (2022) 12 (4): 924–937.

Abstract

KRAS is the most frequently mutated oncogene, harboring mutations in approximately one in seven cancers. Allele-specific KRASG12C inhibitors are currently changing the treatment paradigm for patients with KRASG12C-mutated non-small cell lung cancer and colorectal cancer. The success of addressing a previously elusive KRAS allele has fueled drug discovery efforts for all KRAS mutants. Pan-KRAS drugs have the potential to address broad patient populations, including KRASG12D-, KRASG12V-, KRASG13D-, KRASG12R-, and KRASG12A-mutant or KRAS wild-type-amplified cancers, as well as cancers with acquired resistance to KRASG12C inhibitors. Here, we review actively pursued allele-specific and pan-KRAS inhibition strategies and their potential utility.

Significance: Mutant-selective KRASG12C inhibitors target a fraction (approximately 13.6%) of all KRAS-driven cancers. A broad arsenal of KRAS drugs is needed to comprehensively conquer KRAS-driven cancers. Conceptually, we foresee two future classes of KRAS medicines: mutant-selective KRAS drugs targeting individual variant alleles and pan-KRAS therapeutics targeting a broad range of KRAS alterations.

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Given that pan-KRAS concepts will address extensive unmet needs, a significant effort is now being applied within the pharmaceutical industry to move beyond KRASG12C inhibitors and discover new therapeutics with the ultimate goal to target all KRAS mutants. Exciting progress has already been reported for KRASG12D mutant-selective inhibitors as well as pan-KRAS inhibitors and degraders. We see allele-specific and pan-KRAS drugs as highly complementary therapeutic concepts that can be positioned to comprehensively conquer all KRAS cancers. It remains to be seen whether it will be possible to develop additional mutant-specific inhibitors, such as KRASG12V inhibitors or pan-mutant KRAS inhibitors, that spare wild-type KRAS. We are still at the beginning of drugging KRAS, and KRASG12C inhibitors represent the first chapter of the saga on cracking KRAS. Based on the intense efforts and rapid progress in the field, we see the beginning of the first “beyond KRASG12C” chapter becoming a reality. However, we expect many more chapters need to be written before we have sufficient medicines against KRAS, the Everest of oncogenes (97), for patients with cancer driven by KRAS.

M.H. Hofmann reports grants from Austrian Research Promotion Agency (FFG) during the conduct of the study and is listed as inventor on several patent applications for SOS1 inhibitors and is a full-time employee of Boehringer Ingelheim Regional Center Vienna GmbH & Co KG. D. Gerlach reports grants from Austrian Research Promotion Agency (FFG) during the conduct of the study and is a full-time employee of Boehringer Ingelheim Regional Center Vienna GmbH & Co KG. S. Misale reports other support from Boehringer Ingelheim outside the submitted work. M. Petronczki reports grants from Austrian Research Promotion Agency (FFG) during the conduct of the study and is a full-time employee of Boehringer Ingelheim Regional Center Vienna GmbH & Co KG. N. Kraut reports grants from Austrian Research Promotion Agency (FFG) during the conduct of the study and is a full-time employee of Boehringer Ingelheim Regional Center Vienna GmbH & Co KG.

The authors acknowledge support from Waltraud Pasteiner (Boehringer Ingelheim), Marcelo Marotti (Boehringer Ingelheim), Darryl B. McConnell (Boehringer Ingelheim), Mark Pearson (Boehringer Ingelheim), Markus Johann Bauer (Boehringer Ingelheim), and Mariano Barbacid (Centro Nacional de Investigaciones Oncológicas). Editorial assistance, funded by Boehringer Ingelheim, was provided by Caroline Perry (Ashfield MedComms) and Tracy South (Ashfield MedComms).

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