Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants

Abstract

KRAS is the most frequently mutated oncogene, harboring mutations in approximately one in seven cancers. Allele-specific KRASG12C inhibitors are currently changing the treatment paradigm for patients with KRASG12C-mutated non-small cell lung cancer and colorectal cancer. The success of addressing a previously elusive KRAS allele has fueled drug discovery efforts for all KRAS mutants. Pan-KRAS drugs have the potential to address broad patient populations, including KRASG12D-, KRASG12V-, KRASG13D-, KRASG12R-, and KRASG12A-mutant or KRAS wild-type-amplified cancers, as well as cancers with acquired resistance to KRASG12C inhibitors. Here, we review actively pursued allele-specific and pan-KRAS inhibition strategies and their potential utility.

Significance: Mutant-selective KRASG12C inhibitors target a fraction (approximately 13.6%) of all KRAS-driven cancers. A broad arsenal of KRAS drugs is needed to comprehensively conquer KRAS-driven cancers. Conceptually, we foresee two future classes of KRAS medicines: mutant-selective KRAS drugs targeting individual variant alleles and pan-KRAS therapeutics targeting a broad range of KRAS alterations.

Figure 1.

Overview of the RAS/MAPK signaling pathway and patient numbers/overall cohort prevalence for distinct KRAS alleles/amplification in seven cancer types. A, Schematic representation of KRAS cycling and signaling highlighting selected drug targets and inhibitors. B, Distribution of KRAS alleles/amplification and patient numbers in selected tumor types. Mutation and amplification rates for KRAS have been derived from the AACR GENIE 9.0 public database, whereas patient numbers for the respective tumor types have been extracted from the Cancer Facts & Figures 2000 report published by the American Cancer Society (2). The number of cases for lung adenocarcinoma was set to 40% of all lung cancers. In total, 81,996 distinct samples with mutation and copy number profiles were collapsed into unique patient samples and filtered for distinct alleles and amplification of KRAS. The top seven alleles/amplifications with the highest overall prevalence across tumor types are shown, whereas other mutations are grouped into the class “Other.” The grouping “Multiple” contains all cases, for which different KRAS alterations have been observed in a single patient, for example, two different mutations or a mutation coupled with a KRAS amplification. The “Total” subpanel summarizes the patient numbers for the seven cancer types depicted and ranks the alterations based on overall numbers. Similarly, patient numbers are highlighted for each tumor type and each alteration. The percentages in parentheses reflect the proportion in relation to the full cohort (e.g., 13.6% of all patients with lung adenocarcinoma carry a KRAS^G12C mutation). AMP, amplification; CRC, colorectal cancer; EAC/GEJC, esophageal adenocarcinoma/gastroesophageal junction cancer; IDC, invasive ductal carcinoma; LUAD, lung adenocarcinoma; PDAC, pancreatic ductal adenocarcinoma; STAD, stomach adenocarcinoma; UEC, undifferentiated endometrial carcinoma.

Figure 2.

Percentage of patients who are eligible for FDA-approved precision medicine drugs out of all yearly 1.8 million new cancer cases in the United States. The top five target genes plus KRAS/KRAS^G12C with respect to patient cohort sizes and approved drugs are shown. Drugs against some of these target genes are approved in multiple indications (Supplementary Table S1). Of note, a small percentage of the KRAS segment is currently addressable by the recently approved KRAS^G12C inhibitor sotorasib (yellow); however, the larger portion of KRAS-driven cancer remains unserved (brown). The cohort size of patients benefiting from KRAS-targeting therapies has been derived from non-hematologic cancers mapping major cancer type cohort sizes with the fractions of KRAS-altered (mutated, amplified, multiple) patients in the respective types.

Figure 3.

Distribution of KRAS alterations across all KRAS-driven tumors with a focus on putative benefits (green text) and drawbacks (red text) for mutant-selective and pan-KRAS drugs. The left pie chart shows KRAS alleles that are currently addressable or worked on in non-transparent colors (G12D, G12C, G13C), whereas transparent colors visualize mutated KRAS alleles, which remain elusive to targeted therapy so far. Alleles are color-coded as in Fig. 1, with a long tail of other alleles shown in gray. In total, around 200 distinct KRAS alleles/alterations are reported in the AACR GENIE database. The right pie chart shows all KRAS alterations putatively targetable by pan-KRAS drugs. NCE, New Chemical Entity; WT, wild-type.

Figure 4.

Putative acquired resistance mechanisms detected in KRAS^G12C inhibitor-resistant patients are shown in a schematic pathway diagram. The potential utility of direct and indirect pan-KRAS inhibitors in addressing resistance is indicated using dashed boxes.