KRAS oncogene may be another target conquered in non‐small cell lung cancer (NSCLC)

Abstract

Kirsten rat sarcoma viral oncogene homolog (KRAS) is one of the most common mutant oncogenes in non-small cell lung cancer (NSCLC). The survival of patients with KRAS mutations may be much lower than patients without KRAS mutations. However, due to the complex structure and diverse biological properties, it is difficult to achieve specific inhibitors for the direct elimination of KRAS activity, making KRAS a challenging therapeutic target. At present, with the tireless efforts of medical research, including KRAS G12C inhibitors, immunotherapy and other combination strategies, this dilemma is expected to an end. In addition, inhibition of the downstream signaling pathways of KRAS may be a promising combination strategy. Given the rapid development of treatments, understanding the details will be important to determine the individualized treatment options, including combination therapy and potential resistance mechanisms.

WITHDRAWN: Oncogenic KRASG12Dextrinsically induces an immunosuppressive microenvironment in lung adenocarcinoma

“…Inhibitors for other KRAS mutations have also shown tumor control in preclinical testing and are entering clinical trials, including the KRAS G12D inhibitor MRTX1133 [30]. In fact, clinical use of MRTX1133 is expected to be paradigm shifting for the treatment of NSCLC patients whose tumors bear the G12D mutation: approximately 56% of never smokers and 14% of smokers [31]. Moreover, since 30% of NSCLC patients respond to immunotherapy, the efficacy of combining KRAS G12D inhibitors with immune checkpoint immunotherapy (ICI) is expected to increase.…”

Clinical and Imaging Features of Non-Small Cell Lung Cancer with G12C KRAS Mutation

“…Recently, the KRAS G12C mutation has been identified as a targetable oncogenic mutation in NSCLC with promising investigational agents currently in clinical trials [ 5 , 6 , 20 , 21 ], and one agent, sotorasib, recently receiving accelerated approval by the US FDA [ 9 ]. To the best of our knowledge, this is the first systematic assessment of the imaging features of the primary tumor and patterns of metastasis in NSCLC with the G12C KRAS mutation.…”

“…KRAS cycles between RAS-guanosine triphosphate (GTP)-bound active and RAS-guanosine diphosphate (GDP)-bound inactive states. Until recently, almost no drugs were able to directly target KRAS due to its high affinity for GTP/GDP and the lack of a clear binding pocket [ 5 ]. Recent advances in the development of covalent inhibitors of G12C, which take advantage of the cysteine 12 residue to lock the protein in its inactive GDP bound conformation, have demonstrated promising signals of activity in clinical trials and are poised to dramatically change the treatment landscape for patients with KRAS G12C mutations owing to the relative high frequency of this alteration (approximately 13% of lung cancer) [ 6 , 7 , 8 ].…”

Advancements in NSCLC

“…Following this ephemeral activation, KRAS promptly reverts to its dormant state. 29 , 30 In contrast, under pathologic conditions, an imbalance in KRAS can perpetuate its activation within the EGFR signaling cascade, fostering unrestrained cellular growth and potentially culminating in tumorigenesis. 31 Research indicates that KRAS modulates a variety of cellular activities by engaging several effector proteins.…”

“…In a physiological context, the activation of the EGFR signaling pathway briefly engages KRAS, subsequently transmitting signals to downstream effector proteins. Following this ephemeral activation, KRAS promptly reverts to its dormant state 29,30 . In contrast, under pathologic conditions, an imbalance in KRAS can perpetuate its activation within the EGFR signaling cascade, fostering unrestrained cellular growth and potentially culminating in tumorigenesis 31 .…”