Treatment Strategies for KRAS-Mutated Non-Small-Cell Lung Cancer

Abstract

Activating mutations in KRAS are highly prevalent in solid tumours and are frequently found in 35% of lung, 45% of colorectal, and up to 90% of pancreatic cancers. Mutated KRAS is a prognostic factor for disease-free survival (DFS) and overall survival (OS) in NSCLC and is associated with a more aggressive clinical phenotype, highlighting the need for KRAS-targeted therapy. Once considered undruggable due to its smooth shallow surface, a breakthrough showed that the activated G12C-mutated KRAS isozyme can be directly inhibited via a newly identified switch II pocket. This discovery led to the development of a new class of selective small-molecule inhibitors against the KRAS G12C isoform. Sotorasib and adagrasib are approved in locally advanced or metastatic NSCLC patients who have received at least one prior systemic therapy. Currently, there are at least twelve KRAS G12C inhibitors being tested in clinical trials, either as a single agent or in combination. In this study, KRAS mutation prevalence, subtypes, rates of occurrence in treatment-resistant invasive mucinous adenocarcinomas (IMAs), and novel drug delivery options are reviewed. Additionally, the current status of KRAS inhibitors, multiple resistance mechanisms that limit efficacy, and their use in combination treatment strategies and novel multitargeted approaches in NSCLC are discussed.

Keywords: ACOX2; BRAF; G12C mutation; IMAs; KRAS; NSCLC; adagrasib; drug resistance; sotorasib.

Figure 1

Oncogenic signalling pathways of G12C-mutated KRAS and inhibition by direct inhibitors. Upon receptor tyrosine kinase (RTK) activation, GEFs bind to KRAS and facilitate the exchange of bound-GDP for GTP, thus switching KRAS to its active state. Active KRAS induces signal transduction through MAPK and PI3K pathways, promoting cell proliferation, growth and survival. The G12C mutation blocks GAP binding to KRAS, thus inhibiting GTP hydrolysis and locking G12C-mutant KRAS in its active state. This leads to constitutive activation of the MAPK and PI3K signaling pathways, thus promoting tumorigenesis. Direct KRAS G12C inhibitors (sotorasib and adagrasib) bind GDP bound KRAS and keep it inactive. Image generated using Biorender.com (accessed on 12 January 2023).

Figure 2

Types and prevalence of KRAS mutations in NSCLC adenocarcinoma. In a study of 3026 patients (1128 males (37%) and 1898 females (63%)) with NSCLC adenocarcinoma, 670 patients harboured KRAS mutations. Pie charts demonstrate the frequency of different KRAS mutation subtypes in (a) the entire cohort, (b) females (n = 422), (c) males (n = 248), (d) never smokers (n = 43), (e) former smokers (n = 419), and (f) current smokers (n = 208) [13].

Figure 3

H&E images of (A) invasive mucinous adenocarcinoma and (B) non-mucinous adenocarcinoma of the lung. Invasive mucinous carcinomas have goblet morphology with abundant intracytoplasmic mucin.

Figure 4

Acquired resistance mechanisms to KRAS G12C inhibitors. Image generated using Biorender.com (accessed on 12 January 2023).

Figure 5

Linking ACOX2 expression to mutated KRAS: (A) figure shows prevalence of KRAS mutation across various TCGA datasets. Using Timer 2.0 [97], we analysed the expression of ACOX2 against KRAS (WT vs. mutated) and demonstrate significantly altered expression in (B) LUAD (elevated), (C) LUSC (elevated), (D) PAAD (decreased), (E) COAD (elevated), and (F) READ (elevated). The text in the image generated byTimer 2.0 was adjusted for clarity.