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The Improbable Targeted Therapy: KRAS as an Emerging Target in Non-Small Cell Lung Cancer

KRAS is a frequent oncogenic driver in solid tumors, including non-small cell lung cancer (NSCLC). It was previously thought to be an “undruggable” target due to the lack of deep binding pockets for specific small-molecule inhibitors. A better understanding of the mechanisms that drive KRAS transformation, improved KRAS-targeted drugs, and immunological approaches that aim at yielding immune responses against KRAS neoantigens have sparked a race for approved therapies. Few treatments are available for KRAS mutant NSCLC patients, and several approaches are being tested in clinicals trials to fill this void. Here, we review promising therapeutics tested for KRAS mutant NSCLC.


Introduction

Mutations in Kirsten rat sarcoma viral oncogene homolog (KRAS) are one of the most common genomic alterations identified in solid tumors, especially lung cancer, colorectal cancer, and pancreatic ductal adenocarcinoma (Figure 1). These cancers rely on continued activation and signaling of KRAS, therefore making it an ideal therapeutic target. Unfortunately, therapeutic approaches specifically targeting KRAS, such as attempts to inhibit KRAS membrane localization with farnesyltransferase inhibitors, failed in clinical trials and have thus far not been successful. In non-small lung cancer (NSCLC), the current treatment for KRAS mutant patients relies on chemotherapy, with an average overall survival (OS) of 22 months, which is less than desired.1 Since previous efforts failed to specifically target KRAS, researchers began to indirectly target KRAS through its role in various signaling pathways. Unfortunately, targeting KRAS dependencies in NSCLC has highlighted the difficulty in the effective inhibition of indirect targeting of KRAS.2,3 In addition, downstream pathway blockade of rapidly accelerated fibrosarcoma kinase/mitogen-activated protein kinase/phosphatidylinositol 3-kinase (RAF/MEK/PI3K) with inhibitors has not yet been proven to be effective as shown by the negative results of the Selumetinib Evaluation as Combination Therapy-1 (SELECT-1) trial of selumetinib combined with docetaxel.4, 5, 6 Small-molecule inhibitors have been challenging to develop since mutant KRAS has a very high affinity for guanosine triphosphate (GTP) and the catalytic sites are small and tough to target. Analyses of the KRAS subpopulation in landmark clinical trials in NSCLC have provided information on response (overall response rate of 17%–18%) and survival (median OS of 3 months) of this patient cohort for approved therapeutics,7, 8, 9 but there is still a lack of effective treatments for mutant KRAS. Consequently, the search for therapies that successfully target frequent KRAS mutations has continued due to its large incidence in various cancers.


In < 5 years, the availability of novel therapeutics has transformed the landscape of KRAS treatments, and a target that was once considered “undruggable” now has several therapeutic inhibitors undergoing clinical trials.10, 11, 12 There are essenti