Despite decades of research, efforts to directly target KRAS have been challenging. MRTX849 was identifi ed as a potent, selective, and covalent KRAS G12C inhibitor that exhibits favorable drug-like properties, selectively modifi es mutant cysteine 12 in GDPbound KRAS G12C , and inhibits KRAS-dependent signaling. MRTX849 demonstrated pronounced tumor regression in 17 of 26 (65%) KRAS G12C -positive cell line-and patient-derived xenograft models from multiple tumor types, and objective responses have been observed in patients with KRAS G12C -positive lung and colon adenocarcinomas. Comprehensive pharmacodynamic and pharmacogenomic profi ling in sensitive and partially resistant nonclinical models identifi ed mechanisms implicated in limiting antitumor activity including KRAS nucleotide cycling and pathways that induce feedback reactivation and/or bypass KRAS dependence. These factors included activation of receptor tyrosine kinases (RTK), bypass of KRAS dependence, and genetic dysregulation of cell cycle. Combinations of MRTX849 with agents that target RTKs, mTOR, or cell cycle demonstrated enhanced response and marked tumor regression in several tumor models, including MRTX849-refractory models. SIGNIFICANCE :The discovery of MRTX849 provides a long-awaited opportunity to selectively target KRAS G12C in patients. The in-depth characterization of MRTX849 activity, elucidation of response and resistance mechanisms, and identifi cation of effective combinations provide new insight toward KRAS dependence and the rational development of this class of agents.

No abstract

It is thought that KRAS oncoproteins are constitutively active because their guanosine triphosphatase (GTPase) activity is disabled. Consequently, drugs targeting the inactive or guanosine 5′-diphosphate–bound conformation are not expected to be effective. We describe a mechanism that enables such drugs to inhibit KRASG12C signaling and cancer cell growth. Inhibition requires intact GTPase activity and occurs because drug-bound KRASG12C is insusceptible to nucleotide exchange factors and thus trapped in its inactive state. Indeed, mutants completely lacking GTPase activity and those promoting exchange reduced the potency of the drug. Suppressing nucleotide exchange activity downstream of various tyrosine kinases enhanced KRASG12C inhibition, whereas its potentiation had the opposite effect. These findings reveal that KRASG12C undergoes nucleotide cycling in cancer cells and provide a basis for developing effective therapies to treat KRASG12C-driven cancers.

SUMMARY BRAFV600E drives tumors by dysregulating ERK signaling. In these tumors, we show that high levels of ERK-dependent negative feedback potently suppress ligand-dependent mitogenic signaling and Ras function. BRAFV600E activation is Ras-independent and it signals as a RAF-inhibitor sensitive monomer. RAF inhibitors potently inhibit RAF monomers and ERK signaling, causing relief of ERK-dependent feedback, reactivation of ligand-dependent signal transduction, increased Ras-GTP and generation of RAF inhibitor-resistant RAF dimers. This results in a rebound in ERK activity and culminates in a new steady state, wherein ERK signaling is elevated compared to its initial nadir after RAF inhibition. In this state, ERK signaling is RAF inhibitor resistant, and MEK inhibitor sensitive, and combined inhibition results in enhancement of ERK-pathway inhibition and antitumor activity.

RAF kinase inhibitors have substantial therapeutic effects in patients with BRAF-mutant melanoma. However, only rarely do tumors regress completely, and the therapeutic effects are often temporary. Several mechanisms of resistance to RAF inhibitors have been proposed. The majority of these cause ERK signaling to become insensitive to treatment with RAF inhibitors by increasing the amount of RAF dimers in cells, whereas others bypass the dependence of the tumor on mutant RAF. One motivation for studying mechanisms of drug resistance is that such efforts may suggest new therapeutic targets or rational combination strategies that delay or prevent the emergence of drug-resistant clones. Here, we review the current model of RAF inhibitor resistance with a focus on the implications of this model on ongoing laboratory and clinical efforts to develop more effective therapeutic strategies for patients with BRAF-mutant tumors.

No abstract

KRAS GTPases are activated in one-third of cancers and KRAS G12C is the most common activating alteration in lung adenocarcinoma 1,2 . KRAS G12C inhibitors 3,4 are in Phase-I clinical trials and early data show partial responses in ~50% of lung cancer patients. How cancer cells bypass inhibition, to prevent maximal response to therapy, is not understood. Because KRAS G12C cycles between an active and inactive conformation [4][5][6] , and the inhibitors only bind to the latter, we tested if isogenic cell populations respond non-uniformly by studying the effect of treatment at Reprints and permissions information is available at www.nature.com/reprints.

mutations occur in approximately 25% of patients with non-small cell lung cancer (NSCLC). Despite the uniform presence of mutations, patients with-mutant NSCLC can have a heterogeneous clinical course. As the pattern of co-occurring mutations may describe different biological subsets of patients with -mutant lung adenocarcinoma, we explored the effects of co-occurring mutations on patient outcomes and response to therapy. We identified patients with advanced -mutant NSCLC and evaluated the most common co-occurring genomic alterations. Multivariate analyses were performed incorporating the most frequent co-mutations and clinical characteristics to evaluate association with overall survival as well as response to platinum-pemetrexed chemotherapy and immune checkpoint inhibitors. Among 330 patients with advanced -mutant lung cancers, the most frequent co-mutations were found in (42%), (29%), and/ (27%). In a multivariate analysis, there was a significantly shorter survival in patients with co-mutations in / [HR, 1.96; 95% confidence interval (CI), 1.33-2.92; ≤ 0.001]. (HR, 1.3; = 0.22) and (HR 1.11, = 0.58) co-mutation statuses were not associated with survival. Co-mutation in/ was also associated with shorter duration of initial chemotherapy (HR, 1.64; 95% CI, 1.04-2.59; = 0.03) and shorter overall survival from initiation of immune therapy (HR, 3.54; 95% CI, 1.55-8.11; = 0.003). Among people with -mutant advanced NSCLC,, and / are the most commonly co-occurring somatic genomic alterations. Co-mutation of and/ is an independent prognostic factor, predicting shorter survival, duration of response to initial platinum-based chemotherapy, and survival from the start of immune therapy..