KRAS K117

The recent approval of KRASG12C inhibitors, adagrasib and sotorasib, has validated KRAS as a direct therapeutic target and demonstrated the feasibility of selectively targeting specific RAS mutants. Despite these challenges, new approaches have generated optimism about targeting specific RAS mutations in an allele-dependent manner for cancer therapy, supporting by compelling biochemical and structural evidence, which inspires further exploration of RAS allele-specific vulnerabilities. This review will discuss recent advances and challenges in the development of therapies targeting RAS signaling, highlight emerging therapeutic strategies, and emphasize the importance of allele-specific approaches for leukemia treatment.

Although RasG12V,K147R did not show compelling or quantifiable differences from RasG12V, RasG12V,K117R showed visible and quantifiable suppression compared to RasG12V, and triple mutant RasG12V,K117R,K147R showed dramatic suppression compared to RasG12V and increased suppression compared to RasG12V,K117R. These data are consistent with highly conserved roles for K117 and K147 in Ras activation from flies to mammals.

P1, N=8, Terminated, Boehringer Ingelheim | Completed --> Terminated; Sponsor decision

Taken together, our work provided a comprehensive analysis of driver and targetable alterations in SBA, which can facilitate the practice of precision oncology in this challenging disease.

P1, N=8, Completed, Boehringer Ingelheim | Terminated --> Completed

P1, N=15, Terminated, Boehringer Ingelheim | N=95 --> 15 | Trial completion date: Feb 2024 --> Apr 2022 | Suspended --> Terminated | Trial primary completion date: Jan 2024 --> Apr 2022; Sponsor decision

P1, N=8, Terminated, Boehringer Ingelheim | N=124 --> 8 | Trial completion date: Jul 2024 --> Apr 2022 | Suspended --> Terminated | Trial primary completion date: Oct 2023 --> Apr 2022; Sponsor decision

P1, N=95, Suspended, Boehringer Ingelheim | Recruiting --> Suspended

P1, N=124, Suspended, Boehringer Ingelheim | Recruiting --> Suspended

For the subgroup of patients who carried a KRAS mutation and were treated with bevacizumab and doublet or triplet chemotherapy (N=156), clinical outcome was evaluated and pretreatment tumor burden was quantified as liquid biopsy circulating tumor DNA (ctDNA) mutant allele fraction (MAF) and as total tumor volume (TTV) on CT imaging... Of the 156 patients with a KRAS mutated tumor, most carried a KRAS G12 mutation (N=112, 71.8%), followed by mutations in G13 (N=15, 9.6%), A146 (N=12, 7.7%), Q61 (N=9, 5.8%) and K117 (N=5, 3.2%). High plasma ctDNA levels were observed for patients carrying a KRAS A146 mutation versus those with a KRAS G12 mutation, with a median MAF of 48% versus 19%, respectively. Radiological TTV revealed this difference to be associated with a higher tumor load in patients harboring a KRAS A146 mutation (median TTV 672 cm3 (A146) versus 74 cm3 (G12), p=0.036).

P1, N=95, Recruiting, Boehringer Ingelheim | Trial completion date: Dec 2022 --> Feb 2024 | Trial primary completion date: Oct 2022 --> Jan 2024

Patients with mCRC with a KRAS A146 mutation represent a distinct molecular subgroup of patients with higher tumor burden and worse clinical outcomes, who might benefit from more intensive treatments. These results highlight the importance of testing colorectal cancer for all KRAS mutations in routine clinical care.

P1, N=124, Recruiting, Boehringer Ingelheim | Trial completion date: Sep 2023 --> Jul 2024 | Trial primary completion date: Nov 2022 --> Oct 2023

P1, N=124, Recruiting, Boehringer Ingelheim | Not yet recruiting --> Recruiting

P1, N=124, Not yet recruiting, Boehringer Ingelheim

P1, N=95, Recruiting, Boehringer Ingelheim | Not yet recruiting --> Recruiting

P1, N=95, Not yet recruiting, Boehringer Ingelheim

The clonal and subclonal mutational landscapes of RAS WT pts were analyzed using a mCRC-focused custom ctDNA sequencing panel. Randomized pts (1:1) received mFOLFOX6 plus either panitumumab or bevacizumab. The validated ultra-deep plasma sequencing panel was concordant with tissue sequencing and detected tumor heterogeneity. The PARADIGM study will report the efficacy of anti-EGFR/VEGF therapies; post-treatment collection of ctDNA is ongoing. The relationship between therapeutic effects and clonal and subclonal mutational landscapes will be examined in the future.