Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants

Abstract

KRAS is the most frequently mutated oncogene, harboring mutations in approximately one in seven cancers. Allele-specific KRAS G12C inhibitors are currently changing the treatment paradigm for patients with KRAS G12C -mutated non-small cell lung cancer and colorectal cancer. The success of addressing a previously elusive KRAS allele has fueled drug discovery efforts for all KRAS mutants. Pan-KRAS drugs have the potential to address broad patient populations, including KRAS G12D -, KRAS G12V -, KRAS G13D -, KRAS G12R -, and KRAS G12A -mutant or KRAS wild-typeamplified cancers, as well as cancers with acquired resistance to KRAS G12C inhibitors. Here, we review actively pursued allele-specific and pan-KRAS inhibition strategies and their potential utility.Significance: Mutant-selective KRAS G12C inhibitors target a fraction (approximately 13.6%) of all KRAS-driven cancers. A broad arsenal of KRAS drugs is needed to comprehensively conquer KRASdriven cancers. Conceptually, we foresee two future classes of KRAS medicines: mutant-selective KRAS drugs targeting individual variant alleles and pan-KRAS therapeutics targeting a broad range of KRAS alterations.

Comprehensive Characterization of Human Lung Large Cell Carcinoma Identifies Transcriptomic Signatures with Potential Implications in Response to Immunotherapy

“…Some tumors had molecular aberrations in frequently altered genes in NSCLC such as ALK , EGFR , KRAS or ROS1 , as determined with the TruSight Tumor 170 sequencing panel in-house. However, it is important to emphasize that all these genetic alterations were of uncertain significance in our bioinformatic analysis with the Varsome database, with the exception of a G12C mutation in KRAS , which may lead to treatment adaptation, considering the new KRAS inhibitors under investigation [ 47 ] and the potential utility of targeted therapies in LCC as proposed by previous research [ 8 ]. These specific molecular alterations can be found in Table S2 .…”

Defining An Expanded RAS Conformational Landscape Based on Over 700 Experimentally Determined Structures of KRAS, NRAS, and HRAS

“…RAS proteins are notoriously difficult to drug, because of their conformational variability and lack of deep surface pockets 3,4 . However, through NMR experiments and other techniques, druggable pockets have been identified in certain RAS conformations 55-58 .…”

“…2 ). However, our structural understanding of RAS mutations is incomplete, and, except for KRAS G12C, G12D, and G13C, all mutated RAS forms have not yet been selectively targeted by therapeutics 3,4 .…”

“…In normal tissues, RAS conformational cycling is tightly regulated by the catalytic (CDC25) domain of guanine exchange factors (GEFs; e.g., SOS1), which remove GDP allowing subsequent GTP rebinding 6 , and GTPase activating proteins (GAPs; e.g., NF1), which catalyze the otherwise slow intrinsic rate of GTP hydrolysis to GDP 7 . GEFs and GAPs bind to the conformationally dynamic RAS switch 1 (SW1) and switch 2 (SW2) loops, which also provide binding sites for signal effector proteins 4 (e.g., RAF1) and direct RAS inhibitors 3,8 . RAS targeted therapies mainly bind to an SW1/SW2 pocket (SP12) to block RAS protein interactions or an SW2 pocket (SP2) to lock RAS in an inactive, GDP-bound conformation.…”

Extracellular RNA signatures of mutant KRAS(G12C) lung adenocarcinoma cells

“…Moreover, ~85% of KRAS mutations occur at codons 12, 13, or 61 13 , and mutations at Glycine 12 lock this GTPase in its active, GTP-bound state that enables constitutive oncogenic signaling 11 . Long thought to be undruggable, KRAS(G12C) has been successfully targeted by small molecule inhibitors 15 , including AMG 510, MRTX849, ARS1620, JDQ443, GDC-6036, LY3537982, BI 1823911, and others [16][17][18][19] .…”