New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness

Abstract

In non-small cell lung cancer (NSCLC), the most frequent oncogenic mutation in western countries is KRAS, for which, however, there remains no clinically approved targeted therapies. Recent progress on high biological heterogeneity including diverse KRAS point mutations, varying dependence on mutant KRAS, wide spectrum of other co-occurring genetic alterations, as well as distinct cellular status across the epithelial-to-mesenchymal transition (EMT), has not only deepened our understanding about the pathobiology of KRAS-mutant NSCLC but also brought about unprecedented new hopes for precision treatment of patients. In this review, we provide an update on the most recent advances in KRAS-mutant lung cancer, with a focus on mechanistic insights into tumor heterogeneity, the potential clinic implications and new therapies on horizons tailored for KRAS-mutant lung cancer.

Keywords: KRAS; heterogeneity; immunotherapy; lung cancer; mitogen-activated protein kinases; targeted therapy.

Figure 1

Frequency of KRAS missense mutations. The Cancer Genome Atlas (TCGA) primary lung adenocarcinoma (n = 489; A) and squamous cell carcinoma (n = 492; B) cohorts, and Memorial Sloan Kettering Cancer Center (MSKCC) primary (n = 471; C) and metastatic lung adenocarcinoma (n = 444; D) cohorts.

Figure 2

Oncoprint for common genetic alterations co-occurring with KRAS in TCGA lung adenocarcinoma cohort. (A) The genetic landscape of KRAS, TP53, KEAP1, CDKN2A, and STK11 in TCGA primary lung adenocarcinoma cohort (n = 489). (B) UpSetR plot visualizing the intersections of other mutations co-occurring with KRAS-mutant across TCGA lung adenocarcinomas. The intersection points are indicated by different colors: CDKN2A (purple), KEAP1 (brown), STK11 (blue), and TP53 (orange). Intersections among the co-occurring genes were connected with a line, with frequency of each co-occurring mutation type shown on the bar plot. Set metadata is shown to the left (charts).

Figure 3

MEK mediates the key downstream effect in KRAS-mutant lung cancer cells. (A) Drug information incorporated in the Genomics of Drug Sensitivity in Cancer database. (B) Integrative analysis of drug sensitivity data of KRAS-mutant (n = 20) lung adenocarcinoma cells compared to KRAS-wild-type (WT; n = 40) ones. In the volcano plot, the x-axis indicates the IC50 effect, with effect < 0 representing KRAS-mutation sensitive inhibitors (in blue) compared with KRAS-WT ones. The color intensity and the circle size are proportional to significance value (the y-axis). (C) Sensitivity analysis of KRAS-mutant (in red) and WT (in blue) cells to one of the MEK inhibitors, refametinib.