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The KRAS G12C mutation is present in roughly 3% of all colorectal most cancers circumstances and 1% to 2% of pancreatic adenocarcinoma circumstances, in response to Hao Xie, MD, PhD, a medical oncologist at Mayo Clinic Complete Most cancers Heart.
KRAS G12C inhibitors like sotorasib (Lumakras) and adagrasib (Krazati) have been efficient for some sufferers whose cancers harbor this mutation, however many sufferers’ cancers are proof against remedy despite the fact that that they had no prior publicity to KRAS G12C inhibitors.
By analyzing circulating tumor DNA knowledge from a complete of 14,344 colorectal most cancers sufferers and 5,438 pancreatic ductal adenocarcinoma sufferers from 4 totally different cohorts, Xie’s workforce sought to determine co-occurring genetic alterations that could be chargeable for major resistance to KRAS G12C inhibitors in these cancers.
The work has been printed in Medical Most cancers Analysis.
In sufferers whose cancers possessed the KRAS G12C mutation, the researchers recognized co-occurring alterations with resistance potential in 46.5% of a nationwide colorectal most cancers cohort, 16.4% of a nationwide pancreatic ductal adenocarcinoma cohort, 53.8% of a Mayo Clinic colorectal most cancers cohort, and 36.4% of a Mayo Clinic pancreatic ductal adenocarcinoma cohort.
Probably the most frequent co-occurring alterations in all teams had been different non-G12C KRAS alterations, which had been noticed in at the very least 35.4% of those sufferers’ cancers in each cohort.
Past KRAS, sufferers with KRAS G12C-mutated colorectal cancers had been mostly characterised by alterations together with each level mutations and amplifications of NRAS, BRAF, MAP2K1, and EGFR, whereas MYC amplifications had been current in KRAS G12C-mutated tumors in each pancreatic most cancers affected person cohorts.
Most strikingly, sufferers with pancreatic most cancers whose tumors possessed KRAS G12C and co-occurring mutations related to resistance, together with different non-G12C KRAS alterations, had been discovered to have a four-month median total survival, in comparison with 22 months for these whose pancreatic most cancers had the KRAS G12C mutation however lacked different co-occurring mutations.
Sufferers with pancreatic most cancers whose tumors lacked the KRAS G12C mutation had a median total survival of 25 months.
“The KRAS pathway plays a crucial role in cell biology by regulating cell growth, proliferation, differentiation, and survival,” stated Xie.
“While KRAS signaling is tightly regulated in normal cells, mutations that lead to constantly active signaling, such as KRAS G12C, can lead to cancer progression. Such KRAS mutations are major drivers in many types of cancers, and are also linked to poor prognosis and chemotherapy resistance.”
“These other co-occurring mutations associated with poor prognosis may serve as cellular adaptation and primary resistance mechanisms, and may explain the limited efficacy of KRAS G12C inhibitor monotherapy,” Xie stated.
“Their presence also indicates the higher level of tumor heterogeneity in colorectal and pancreatic cancers, and emphasizes the importance of sequencing tumors with the KRAS G12C mutation for co-occurring resistance alterations.”
“KRAS G12C inhibitors are very promising, but they are not a panacea for these types of cancers. Patients and their doctors need to be aware of the current limitations.”
Limitations of the research embrace its retrospective nature and that tumor genetic knowledge was acquired by way of liquid biopsy, which has the benefit of reflecting tumor heterogeneity however could also be restricted by tumor DNA shedding.
Extra data:
Identification of Candidate Alterations Mediating KRASG12C Inhibitor Resistance in Superior Colorectal and Pancreatic Cancers, Medical Most cancers Analysis (2025). DOI: 10.1158/1078-0432.CCR-24-2948
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American Affiliation for Most cancers Analysis
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Sure genetic alterations could contribute to major resistance of sure cancers to KRAS G12C inhibitors (2025, March 3)
retrieved 3 March 2025
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