Kirsten rat sarcoma inhibitors in clinical development against nonsmall cell lung cancer

Abstract

Purpose of reviewThe unique structure made Kirsten rat sarcoma (KRAS) 'undruggable' for quite an extended period. The functional mechanism of this small protein is well illustrated. However, there is no precision medicine for nonsmall cell lung cancer (NSCLC) patients burden with KRAS mutation. The attempts made by scientists to make challenge history against KRAS mutation and their druggable targets are worth elucidating. Recent findingsThe appearance of orphan drug AMG510 in the market specifically targeting KRAS G12C is a tremendous breakthrough. Several KRAS inhibitors are under development now. More studies focus on combo treatment of KRAS inhibition and immune checkpoint inhibitors (ICIs). Recent preclinical and clinical investigations have been reported that NSCLC patients with KRAS mutation can benefit from ICIs.

Daily Practice Assessment of KRAS Status in NSCLC Patients: A New Challenge for the Thoracic Pathologist Is Right around the Corner

“…Moreover, besides the different promising ICIs, new molecules are currently being evaluated in many clinical trials and recent results suggest the coming soon administration of additional targeted therapies for NS-NSCLC in daily practice [ 10 , 12 , 14 , 15 , 16 , 17 ]. Among these new drugs, some target KRAS mutations, particularly the KRAS G12C mutation [ 18 , 19 , 20 , 21 ]. The development of these therapies raises a lot of hope and expectations in thoracic oncology since the KRAS mutations, which have been considered for a long time as non-targetable, are identified in more than 30% of NSCLC patients, at least in Europe and in the US, depending on the different populations [ 15 , 22 , 23 , 24 , 25 , 26 , 27 ].…”

Cancer/Testis Antigens as Biomarker and Target for the Diagnosis, Prognosis, and Therapy of Lung Cancer

“…It is well established that lung cancer patients harbour many driver gene mutations, such as K-ras ( 6 , 7 ), EGFR ( 8 ), EML4-ALK ( 9 ), and CLIP1-LTK ( 10 ), which contribute to the initiation and progression of lung cancer. Accordingly, several oncogenic genes have been used as biomarkers for lung cancer diagnosis; however, the sensitivities of K-ras-G12C, EGFR, EML4-ALK, and CLIP1-LTK in lung cancer patients are only 14%, 46%, 4%, and 0.5%, respectively ( 6 – 10 ). K-ras-G12C and EGFR-targeted therapeutics against lung cancer appear promising in patients with these mutants and have prolonged survival time in the short term ( 6 , 8 , 10 ).…”

“…Accordingly, several oncogenic genes have been used as biomarkers for lung cancer diagnosis; however, the sensitivities of K-ras-G12C, EGFR, EML4-ALK, and CLIP1-LTK in lung cancer patients are only 14%, 46%, 4%, and 0.5%, respectively ( 6 – 10 ). K-ras-G12C and EGFR-targeted therapeutics against lung cancer appear promising in patients with these mutants and have prolonged survival time in the short term ( 6 , 8 , 10 ). However, the 5-year overall survival rate of lung cancer patients has only improved from 16% 10 years ago to 18% now, implying that merely targeting these mutant genes is not enough to conquer lung cancer ( 1 – 5 , 11 , 12 ).…”

Editorial: Lung cancer: continuous progress in diagnosis and treatment

“…Mechanisms involved in resistance to osimertinib and novel targeted therapies in clinical development are described in the article by Zeng et al [16]. KRAS inhibitors are described by Li et al [17]. Rare mutations and their corresponding targeted drugs are summarized by Kauffmann-Guerrero and Tufman [18].…”