Targeting Mutated KRAS Genes to Treat Solid Tumours

Abstract

Kirsten rat sarcoma (KRAS) is one of the most frequently mutated oncogenes in solid tumours. It encodes an important signalling pathway that drives cellular proliferation and growth. It is frequently mutated in aggressive advanced solid tumours, particularly colorectal, lung and pancreatic cancer. Since the first mutated KRAS was discovered in the 1980s, decades of research to develop targeted inhibitors of mutant KRAS have fallen short of the task, until recently. Multiple agents are now in clinical trials, including specific mutant KRAS inhibitors, pan-KRAS inhibitors, therapeutic vaccines and other targeted inhibitors. Mutant-specific KRAS G12C inhibitors are the most advanced, with two inhibitors, adagrasib and sotorasib, achieving approval in 2021 for the second-line treatment of patients with KRAS G12C mutant lung cancer. In this review, we summarise the importance of mutant KRAS in solid tumours, prior attempts at inhibiting mutant KRAS, and the current promising targeted agents being investigated in clinical trials, along with future challenges.

Indoloquinoline-Mediated Targeted Downregulation of KRAS through Selective Stabilization of the Mid-Promoter G-Quadruplex Structure

“…KRAS is a well-validated therapeutic target in oncology, and one that is no longer considered “undruggable”, with the new clinical agents that target the G12C mutant protein [ 64 ]. While the development of sotorasib and adagrasib are remarkable, G12C is common only in non-small cell lung cancer, and these drugs are not utilized in pancreatic or colorectal cancers often [ 65 , 66 ]. Moreover, neither compound has benefits for patients with KRAS amplification or overexpression, so there remains a need for the development of novel compounds that can modulate KRAS.…”

Pancreatic Cancer: Pathogenesis, Screening, Diagnosis, and Treatment

“…156 Although the advancement of KRAS G12C inhibitors is impactful for treatment of certain cancers, such as lung cancer, this mutation is relatively rare in pancreatic cancer, which primarily has G12D and G12V mutations. Other innovative KRAS inhibition approaches, including Pan KRAS inhibitors that target the guanine exchange factor SOS1 (BI 1701963), 157 a number of SHP2 inhibitors, and combination therapies including KRAS-specific vaccines 158 may benefit patients with pancreatic cancer in the future. A promising G12D-specific inhibitor, MRTX1133, is also poised to undergo clinical testing in 2022.…”

Targeted therapy for pancreatic ductal adenocarcinoma: Mechanisms and clinical study

“… 302 , 303 , 304 , 305 However, multiple inhibitors targeting other KRAS mutations, pan‐KRAS inhibitors, SHP2 inhibitors, and therapeutic vaccines targeting KRAS are under development and testing. 306 MRTX1133, a promising, novel KRAS G12D inhibitor, is awaiting clinical trial after having shown preclinical efficacy—eight out of 11 KRAS G12D ‐mutated cell line xenografts and patient‐derived xenografts showed tumor regression after MRTX1133 treatment. 47 , 307 BI 1701963 , which is currently under phase I trial, is a pan‐KRAS inhibitor that disrupts the binding of KRAS to GEFs SOS1.…”

“…And while in 2021, Sotorasib (AMG510) and Adagrasib (MRTX849) received FDA approval and FDA breakthrough therapy designation respectively, the impact of these inhibitors will be limited as KRAS G12C mutation is only present in 1% in PDAC cases 302–305 . However, multiple inhibitors targeting other KRAS mutations, pan‐KRAS inhibitors, SHP2 inhibitors, and therapeutic vaccines targeting KRAS are under development and testing 306 . MRTX1133, a promising, novel KRAS G12D inhibitor, is awaiting clinical trial after having shown preclinical efficacy—eight out of 11 KRAS G12D ‐mutated cell line xenografts and patient‐derived xenografts showed tumor regression after MRTX1133 treatment 47,307 .…”