Abstract
Non-small-cell lung cancer (NSCLC) with Kirsten rat sarcoma (KRAS) mutations has notoriously challenged oncologists and researchers for three notable reasons: (1) the historical assumption that KRAS is “undruggable”, (2) the disease heterogeneity and (3) the shaping of the tumor microenvironment by KRAS downstream effector functions. Better insights into KRAS structural biochemistry allowed researchers to develop direct KRAS(G12C) inhibitors, which have shown early signs of clinical activity in NSCLC patients and have recently led to an FDA breakthrough designation for AMG-510. Following the approval of immune checkpoint inhibitors for PDL1-positive NSCLC, this could fuel yet another major paradigm shift in the treatment of advanced lung cancer. Here, we review advances in our understanding of the biology of direct KRAS inhibition and project future opportunities and challenges of dual KRAS and immune checkpoint inhibition. This strategy is supported by preclinical models which show that KRAS(G12C) inhibitors can turn some immunologically “cold” tumors into “hot” ones and therefore could benefit patients whose tumors harbor subtype-defining STK11/LKB1 co-mutations. Forty years after the discovery of KRAS as a transforming oncogene, we are on the verge of approval of the first KRAS-targeted drug combinations, thus therapeutically unifying Paul Ehrlich’s century-old “magic bullet” vision with Rudolf Virchow’s cancer inflammation theory.
Highlights
MAPK pathway feedback reactivation [65,66,67,68]. These drug combinations are effective in preclinical models if applied on intermittent treatment schedules, but future clinical trials will have to clarify if this approach can overcome therapeutic limitations and toxicities observed with continuous MEK inhibition
Response rates are slightly inferior to those observed with other oncogene-targeted therapies
EML4/ALK) in pretreated patients, and differences in response rates could be due to the heterogeneity of Kirsten rat sarcoma (KRAS)-mutant lung tumors with multiple DNA-damage-associated genomic alterations [128,129,130,131]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. In contrast to clinically approved oncogene-targeted therapies for various other malignancies, e.g., imatinib for BCR/ABL-positive chronic myeloid leukemia (CML) or EGFR and ALK inhibitors for EGFR-mutant and EML4/ALKrearranged NSCLC, respectively [11,12,13,14], the development of a “magic bullet” against mutant KRAS has remarkably challenged scientists and physicians alike because it had long been considered “undruggable” due to biochemistry constraints [15] Another reason for the aggressive behavior and difficulty in treating KRAS-mutant lung cancer is its highly inflammatory phenotype [16]. In the century to follow, our mechanistic understanding of the bidirectional interaction between epithelial cancer and immune cells remained incomplete, and the molecular mechanisms that make inflammatory processes an important cofactor in carcinogenesis, tumor maintenance and metastasis have only recently begun to unravel [19,20]
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