Certain genetic alterations may contribute to primary resistance of certain cancers to KRAS G12C inhibitors

The KRAS G12C mutation is found in approximately 3% of all colorectal cancer cases and 1% to 2% of pancreatic adenocarcinoma cases, according to Hao Xie, MD, PhD, a medical oncologist at Mayo Clinic Comprehensive Cancer Center.

KRAS G12C inhibitors like sotorasib (Lumakras) and adagrasib (Krazati) have been effective for some patients whose cancers harbor this mutation, but many patients’ cancers are resistant to therapy even though they had no prior exposure to KRAS G12C inhibitors.

By analyzing circulating tumor DNA data from a total of 14,344 colorectal cancer patients and 5,438 pancreatic ductal adenocarcinoma patients from four different cohorts, Xie’s team sought to identify co-occurring genetic alterations that might be responsible for primary resistance to KRAS G12C inhibitors in these cancers.

The work has been published in Clinical Cancer Research.

In patients whose cancers possessed the KRAS G12C mutation, the researchers identified co-occurring alterations with resistance potential in 46.5% of a national colorectal cancer cohort, 16.4% of a national pancreatic ductal adenocarcinoma cohort, 53.8% of a Mayo Clinic colorectal cancer cohort, and 36.4% of a Mayo Clinic pancreatic ductal adenocarcinoma cohort.

The most frequent co-occurring alterations in all groups were other non-G12C KRAS alterations, which were observed in at least 35.4% of these patients’ cancers in every cohort.

Beyond KRAS, patients with KRAS G12C-mutated colorectal cancers were most commonly characterized by alterations including both point mutations and amplifications of NRAS, BRAF, MAP2K1, and EGFR, whereas MYC amplifications were present in KRAS G12C-mutated tumors in both pancreatic cancer patient cohorts.

Most strikingly, patients with pancreatic cancer whose tumors possessed KRAS G12C and co-occurring mutations associated with resistance, including other non-G12C KRAS alterations, were found to have a four-month median overall survival, compared to 22 months for those whose pancreatic cancer had the KRAS G12C mutation but lacked other co-occurring mutations.

Patients with pancreatic cancer whose tumors lacked the KRAS G12C mutation had a median overall survival of 25 months.

“The KRAS pathway plays a crucial role in cell biology by regulating cell growth, proliferation, differentiation, and survival,” said 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 said.

“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 study include its retrospective nature and that tumor genetic data was acquired via liquid biopsy, which has the advantage of reflecting tumor heterogeneity but may be limited by tumor DNA shedding.

The KRAS G12C mutation is found in approximately 3% of all colorectal cancer cases and 1% to 2% of pancreatic adenocarcinoma cases, according to Hao Xie, MD, PhD, a medical oncologist at Mayo Clinic Comprehensive Cancer Center.

KRAS G12C inhibitors like sotorasib (Lumakras) and adagrasib (Krazati) have been effective for some patients whose cancers harbor this mutation, but many patients’ cancers are resistant to therapy even though they had no prior exposure to KRAS G12C inhibitors.

By analyzing circulating tumor DNA data from a total of 14,344 colorectal cancer patients and 5,438 pancreatic ductal adenocarcinoma patients from four different cohorts, Xie’s team sought to identify co-occurring genetic alterations that might be responsible for primary resistance to KRAS G12C inhibitors in these cancers.

The work has been published in Clinical Cancer Research.

In patients whose cancers possessed the KRAS G12C mutation, the researchers identified co-occurring alterations with resistance potential in 46.5% of a national colorectal cancer cohort, 16.4% of a national pancreatic ductal adenocarcinoma cohort, 53.8% of a Mayo Clinic colorectal cancer cohort, and 36.4% of a Mayo Clinic pancreatic ductal adenocarcinoma cohort.

The most frequent co-occurring alterations in all groups were other non-G12C KRAS alterations, which were observed in at least 35.4% of these patients’ cancers in every cohort.

Beyond KRAS, patients with KRAS G12C-mutated colorectal cancers were most commonly characterized by alterations including both point mutations and amplifications of NRAS, BRAF, MAP2K1, and EGFR, whereas MYC amplifications were present in KRAS G12C-mutated tumors in both pancreatic cancer patient cohorts.

Most strikingly, patients with pancreatic cancer whose tumors possessed KRAS G12C and co-occurring mutations associated with resistance, including other non-G12C KRAS alterations, were found to have a four-month median overall survival, compared to 22 months for those whose pancreatic cancer had the KRAS G12C mutation but lacked other co-occurring mutations.

Patients with pancreatic cancer whose tumors lacked the KRAS G12C mutation had a median overall survival of 25 months.

“The KRAS pathway plays a crucial role in cell biology by regulating cell growth, proliferation, differentiation, and survival,” said 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 said.

“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 study include its retrospective nature and that tumor genetic data was acquired via liquid biopsy, which has the advantage of reflecting tumor heterogeneity but may be limited by tumor DNA shedding.