If Virchow and Ehrlich Had Dreamt Together: What the Future Holds for -Mutant Lung Cancer.

Non-small-cell lung cancer (NSCLC) with Kirsten rat sarcoma () mutations has notoriously challenged oncologists and researchers for three notable reasons: (1) the historical assumption that is "undruggable", (2) the disease heterogeneity and (3) the shaping of the tumor microenvironment by downstream effector functions. Better insights into structural biochemistry allowed researchers to develop direct (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 inhibition and project future opportunities and challenges of dual and immune checkpoint inhibition. This strategy is supported by preclinical models which show that (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 as a transforming oncogene, we are on the verge of approval of the first -targeted drug combinations, thus therapeutically unifying Paul Ehrlich's century-old "magic bullet" vision with Rudolf Virchow's cancer inflammation theory.