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The current landscape of using direct inhibitors to target KRAS^G12C-mutated NSCLC.

ABSTRACT: Mutation in KRAS protooncogene represents one of the most common genetic alterations in NSCLC and has posed a great therapeutic challenge over the past ~ 40 years since its discovery. However, the pioneer work from Shokat's lab in 2013 has led to a recent wave of direct KRAS^G12C inhibitors that utilize the switch II pocket identified. Notably, two of the inhibitors have recently received US FDA approval for their use in the treatment of KRAS^G12C mutant NSCLC. Despite this success, there remains the challenge of combating the resistance that cell lines, xenografts, and patients have exhibited while treated with KRAS^G12C inhibitors. This review discusses the varying mechanisms of resistance that limit long-lasting effective treatment of those direct inhibitors and highlights several novel therapeutic approaches including a new class of KRAS^G12C (ON) inhibitors, combinational therapies across the same and different pathways, and combination with immunotherapy/chemotherapy as possible solutions to the pressing question of adaptive resistance.

SUBMITTER: Batrash F

PROVIDER: S-EPMC10625227 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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The current landscape of using direct inhibitors to target KRASG12C-mutated NSCLC.

Batrash Firas F Kutmah Mahmoud M Zhang Jun J

Experimental hematology & oncology 20231104 1

Mutation in KRAS protooncogene represents one of the most common genetic alterations in NSCLC and has posed a great therapeutic challenge over the past ~ 40 years since its discovery. However, the pioneer work from Shokat's lab in 2013 has led to a recent wave of direct KRASG12C inhibitors that utilize the switch II pocket identified. Notably, two of the inhibitors have recently received US FDA approval for their use in the treatment of KRASG12C mutant NSCLC. Despite this s ...[more]

PMID: 37925476

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Project description:PurposePromising single-agent activity from sotorasib and adagrasib in KRASG12C-mutant tumors has provided clinical evidence of effective KRAS signaling inhibition. However, comprehensive analysis of KRAS-variant prevalence, genomic alterations, and the relationship between KRAS and immuno-oncology biomarkers is lacking.Materials and methodsRetrospective analysis of deidentified records from 79,004 patients with various cancers who underwent next-generation sequencing was performed. Fisher's exact test evaluated the association between cancer subtypes and KRAS variants. Logistic regression assessed KRASG12C comutations with other oncogenes and the association between KRAS variants and immuno-oncology biomarkers.ResultsOf the 79,004 samples assessed, 13,758 (17.4%) harbored KRAS mutations, with 1,632 (11.9%) harboring KRASG12C and 12,126 (88.1%) harboring other KRAS variants (KRASnon-G12C). Compared with KRASnon-G12C across all tumor subtypes, KRASG12C was more prevalent in females (56% v 51%, false discovery rate-adjusted P value [FDR-P] = .0006), current or prior smokers (85% v 56%, FDR-P < .0001), and patients age > 60 years (73% v 63%, FDR-P ≤ .0001). The most frequent KRAS variants across all subtypes were G12D (29.5%), G12V (23.0%), G12C (11.9%), G13D (6.5%), and G12R (6.2%). KRASG12C was most prevalent in patients with non-small-cell lung cancer (9%), appendiceal (3.9%), colorectal (3.2%), tumor of unknown origin (1.6%), small bowel (1.43%), and pancreatic (1.3%) cancers. Compared with KRASnon-G12C-mutated, KRASG12C-mutated tumors were significantly associated with tumor mutational burden-high status (17.9% v 8.4%, odds ratio [OR] = 2.38; FDR-P < .0001). KRASG12C-mutated tumors exhibited a distinct comutation profile from KRASnon-G12C-mutated tumors, including higher comutations of STK11 (20.59% v 5.95%, OR = 4.10; FDR-P < .01) and KEAP1 (15.38% v 4.61%, OR = 3.76; FDR-P < .01).ConclusionThis study presents the first large-scale, pan-cancer genomic characterization of KRASG12C. The KRASG12C mutation was more prevalent in females and older patients and appeared to be associated with smoking status. KRASG12C tumors exhibited a distinct comutation profile and were associated with tumor mutational burden-high status.

Dataset Information

The current landscape of using direct inhibitors to target KRAS^G12C-mutated NSCLC.

Publications

The current landscape of using direct inhibitors to target KRAS<sup>G12C</sup>-mutated NSCLC.

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