Targeting KRAS mutant cancers: from druggable therapy to drug resistance

Abstract

Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) is the most frequently mutated oncogene, occurring in a variety of tumor types. Targeting KRAS mutations with drugs is challenging because KRAS is considered undruggable due to the lack of classic drug binding sites. Over the past 40 years, great efforts have been made to explore routes for indirect targeting of KRAS mutant cancers, including KRAS expression, processing, upstream regulators, or downstream effectors. With the advent of KRAS (G12C) inhibitors, KRAS mutations are now druggable. Despite such inhibitors showing remarkable clinical responses, resistance to monotherapy of KRAS inhibitors is eventually developed. Significant progress has been made in understanding the mechanisms of drug resistance to KRAS-mutant inhibitors. Here we review the most recent advances in therapeutic approaches and resistance mechanisms targeting KRAS mutations and discuss opportunities for combination therapy.

Evaluation of AMG510 Therapy on KRAS-Mutant Non–Small Cell Lung Cancer and Colorectal Cancer Cell Using a 3D Invasive Tumor Spheroid System under Normoxia and Hypoxia

“…Significant volume reduction was found in samples with concentrations of AMG510 over 0.01 μM as shown in Figure 3 a. In pre-clinical analysis, AMG510 treatment led to the regression of KRAS tumors [ 25 , 26 ]. The cell viability detected by the Alamar Blue assay ( Figure 3 (bI)) inhibited an obvious reduction with the increased concentration; the day 7 data comparison ( Figure 3 (bII)) enhanced the confidence level.…”

Role of RAS signaling in ovarian cancer

“…This includes mutations within the drug binding pockets, new KRASG12C protein production, feedback activations of the KRAS pathway, activation of both upstream and downstream mediators, etc. 179 KRAS mutation is a predictive marker of poor response to anti-EGFR monoclonal antibody therapies. [180][181][182][183] In a molecular profiling study with 55 patients with EOC, 35% were found to have ≥1 somatic mutation, including 23 KRAS and six NRAS.…”

“…This includes mutations within the drug binding pockets, new KRASG12C protein production, feedback activations of the KRAS pathway, activation of both upstream and downstream mediators, etc. 179 KRAS mutation is a predictive marker of poor response to anti-EGFR monoclonal antibody therapies. 180 – 183 …”

The Oxidative Drug Combination for Suppressing KRAS G12D Inducible Tumour Growth

“…RAS interacts with proteins involved in many cellular processes, including cell growth, differentiation, mitosis, and metabolism. These interactions lead to the activation of effector proteins such as Raf kinase, PI3K, and Akt, which have been found to have important roles in tumour formation [8,9]. Inhibition of KRAS signalling has been considered as a promising therapeutic strategy.…”