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Studies in KRAS-mutant lung and pancreatic adenocarcinoma and in KRAS-amplified gastric carcinoma reveal that SHP2 inhibition augments the antitumor effect of MEK inhibitor treatment., Author(s): Trang T. Mai [sup.1] , Piro Lito [sup.1] [sup.2] Author Affiliations: (1) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, USA (2) Weill Cornell Medical [...]

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 [...]

Approximately 3.4 million patients worldwide are diagnosed each year with cancers that have pathogenic mutations in one of three RAS proto-oncogenes (KRAS, NRAS and HRAS) 1,2 . These mutations impair the GTPase activity of RAS, leading to activation of downstream signalling and proliferation 3-6 . Long-standing efforts to restore the hydrolase activity of RAS mutants have been unsuccessful, extinguishing any consideration towards a viable therapeutic strategy 7 . Here we show that tri-complex inhibitors-that is, molecular glues with the ability to recruit cyclophilin A (CYPA) to the active state of RAS-have a dual mechanism of action: not only do they prevent activated RAS from binding to its effectors, but they also stimulate GTP hydrolysis. Drug-bound CYPA complexes modulate residues in the switch II motif of RAS to coordinate the nucleophilic attack on the γ-phosphate of GTP in a mutation-specific manner. RAS mutants that were most sensitive to stimulation of GTPase activity were more susceptible to treatment than mutants in which the hydrolysis could not be enhanced, suggesting that pharmacological stimulation of hydrolysis potentiates the therapeutic effects of tri-complex inhibitors for specific RAS mutants. This study lays the foundation for developing a class of therapeutics that inhibit cancer growth by stimulating mutant GTPase activity., Competing Interests: Competing interests: P.L. is listed as an inventor on patents filed by MSKCC regarding treatment of KRAS- or BRAF-mutant cancers; reports grants to his institution from Revolution Medicines, Amgen, Mirati and Boehringer Ingelheim; and reports consulting fees or honoraria from Black Diamond Therapeutics, AmMax, OrbiMed, PAQ-Tx, Repare Therapeutics, Boehringer Ingelheim, Menarini Group and Revolution Medicines, as well as membership on the scientific advisory board of Frontier Medicines, Ikena, Biotheryx and PAQ-Tx (consulting fees and equity in each). The other authors declare no competing interests., (© 2024. The Author(s).)

Cancer driver mutations often show distinct temporal acquisition patterns, but the biological basis for this, if any, remains unknown. RAS mutations occur invariably late in the course of acute myeloid leukaemia, upon progression or relapsed/refractory disease 1-6 . Here, by using human leukaemogenesis models, we first show that RAS mutations are obligatory late events that need to succeed earlier cooperating mutations. We provide the mechanistic explanation for this in a requirement for mutant RAS to specifically transform committed progenitors of the myelomonocytic lineage (granulocyte-monocyte progenitors) harbouring previously acquired driver mutations, showing that advanced leukaemic clones can originate from a different cell type in the haematopoietic hierarchy than ancestral clones. Furthermore, we demonstrate that RAS-mutant leukaemia stem cells (LSCs) give rise to monocytic disease, as observed frequently in patients with poor responses to treatment with the BCL2 inhibitor venetoclax. We show that this is because RAS-mutant LSCs, in contrast to RAS-wild-type LSCs, have altered BCL2 family gene expression and are resistant to venetoclax, driving clinical resistance and relapse with monocytic features. Our findings demonstrate that a specific genetic driver shapes the non-genetic cellular hierarchy of acute myeloid leukaemia by imposing a specific LSC target cell restriction and critically affects therapeutic outcomes in patients., Competing Interests: Competing interests: M.K. receives research support from Klondike, AbbVie and Janssen, and consulting fees from AbbVie, Syndax, Novartis, Servier, AbbVie, Menarini-Stemline Therapeutics, Adaptive, Dark Blue Therapeutics, MEI Pharma, Legend Biotech, Sanofi Aventis, Auxenion GmbH, Vincerx, Curis, Intellisphere and Janssen. D.A.L. is an advisory board member of Mission Bio, Veracyte, Pangea and Alethiomics and has received research support from Ultima Genomics unrelated to this work. A.M. receives research support from Chimeric Therapeutics, Lin Biosciences, Hibercell Inc., Qurient and Molecular Templates, Inc. C.D.D. has received consulting fees from Abbvie, AstraZeneca, Astellas, GenMab, Notable Labs, Rigel and Servier. E.P. is cofounder of, and holds a fiduciary role in Isabl Inc. P.L. has received grants to his Institution from Amgen, Mirati, Revolution Medicines, Boehringer Ingelheim and Virtec Pharmaceuticals. P.L. is an advisory board member of Frontier Medicines, Ikena, Biotheryx and PAQ-Tx (consulting fees and equity in each) and has received consulting fees or honoraria from Black Diamond Therapeutics, AmMax, OrbiMed, PAQ-Tx, Repare Therapeutics, Boehringer Ingelheim and Revolution Medicines. EPP has received consulting fees or honoraria from Janssen, Daiichi Sankyo and Cellarity, unrelated to the current study. The other authors declare no competing interests., (© 2024. The Author(s).)

RAS oncogenes (collectively NRAS, HRAS and especially KRAS) are among the most frequently mutated genes in cancer, with common driver mutations occurring at codons 12, 13 and 61 1 . Small molecule inhibitors of the KRAS(G12C) oncoprotein have demonstrated clinical efficacy in patients with multiple cancer types and have led to regulatory approvals for the treatment of non-small cell lung cancer 2,3 . Nevertheless, KRAS G12C mutations account for only around 15% of KRAS-mutated cancers 4,5 , and there are no approved KRAS inhibitors for the majority of patients with tumours containing other common KRAS mutations. Here we describe RMC-7977, a reversible, tri-complex RAS inhibitor with broad-spectrum activity for the active state of both mutant and wild-type KRAS, NRAS and HRAS variants (a RAS(ON) multi-selective inhibitor). Preclinically, RMC-7977 demonstrated potent activity against RAS-addicted tumours carrying various RAS genotypes, particularly against cancer models with KRAS codon 12 mutations (KRAS G12X ). Treatment with RMC-7977 led to tumour regression and was well tolerated in diverse RAS-addicted preclinical cancer models. Additionally, RMC-7977 inhibited the growth of KRAS G12C cancer models that are resistant to KRAS(G12C) inhibitors owing to restoration of RAS pathway signalling. Thus, RAS(ON) multi-selective inhibitors can target multiple oncogenic and wild-type RAS isoforms and have the potential to treat a wide range of RAS-addicted cancers with high unmet clinical need. A related RAS(ON) multi-selective inhibitor, RMC-6236, is currently under clinical evaluation in patients with KRAS-mutant solid tumours (ClinicalTrials.gov identifier: NCT05379985)., (© 2024. The Author(s).)

KRAS is one of the most commonly mutated proteins in cancer, and efforts to directly inhibit its function have been continuing for decades. The most successful of these has been the development of covalent allele-specific inhibitors that trap KRAS G12C in its inactive conformation and suppress tumour growth in patients 1-7 . Whether inactive-state selective inhibition can be used to therapeutically target non-G12C KRAS mutants remains under investigation. Here we report the discovery and characterization of a non-covalent inhibitor that binds preferentially and with high affinity to the inactive state of KRAS while sparing NRAS and HRAS. Although limited to only a few amino acids, the evolutionary divergence in the GTPase domain of RAS isoforms was sufficient to impart orthosteric and allosteric constraints for KRAS selectivity. The inhibitor blocked nucleotide exchange to prevent the activation of wild-type KRAS and a broad range of KRAS mutants, including G12A/C/D/F/V/S, G13C/D, V14I, L19F, Q22K, D33E, Q61H, K117N and A146V/T. Inhibition of downstream signalling and proliferation was restricted to cancer cells harbouring mutant KRAS, and drug treatment suppressed KRAS mutant tumour growth in mice, without having a detrimental effect on animal weight. Our study suggests that most KRAS oncoproteins cycle between an active state and an inactive state in cancer cells and are dependent on nucleotide exchange for activation. Pan-KRAS inhibitors, such as the one described here, have broad therapeutic implications and merit clinical investigation in patients with KRAS-driven cancers., (© 2023. The Author(s).)

Inactive state-selective KRAS(G12C) inhibitors 1-8 demonstrate a 30-40% response rate and result in approximately 6-month median progression-free survival in patients with lung cancer 9 . The genetic basis for resistance to these first-in-class mutant GTPase inhibitors remains under investigation. Here we evaluated matched pre-treatment and post-treatment specimens from 43 patients treated with the KRAS(G12C) inhibitor sotorasib. Multiple treatment-emergent alterations were observed across 27 patients, including alterations in KRAS, NRAS, BRAF, EGFR, FGFR2, MYC and other genes. In preclinical patient-derived xenograft and cell line models, resistance to KRAS(G12C) inhibition was associated with low allele frequency hotspot mutations in KRAS(G12V or G13D), NRAS(Q61K or G13R), MRAS(Q71R) and/or BRAF(G596R), mirroring observations in patients. Single-cell sequencing in an isogenic lineage identified secondary RAS and/or BRAF mutations in the same cells as KRAS(G12C), where they bypassed inhibition without affecting target inactivation. Genetic or pharmacological targeting of ERK signalling intermediates enhanced the antiproliferative effect of G12C inhibitor treatment in models with acquired RAS or BRAF mutations. Our study thus suggests a heterogenous pattern of resistance with multiple subclonal events emerging during G12C inhibitor treatment. A subset of patients in our cohort acquired oncogenic KRAS, NRAS or BRAF mutations, and resistance in this setting may be delayed by co-targeting of ERK signalling intermediates. These findings merit broader evaluation in prospective clinical trials., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

KRAS GTPases are activated in one-third of cancers, and KRAS(G12C) is one of the most common activating alterations in lung adenocarcinoma 1,2 . KRAS(G12C) inhibitors 3,4 are in phase-I clinical trials and early data show partial responses in nearly half of patients with lung cancer. How cancer cells bypass inhibition to prevent maximal response to therapy is not understood. Because KRAS(G12C) cycles between an active and inactive conformation 4-6 , and the inhibitors bind only to the latter, we tested whether isogenic cell populations respond in a non-uniform manner by studying the effect of treatment at a single-cell resolution. Here we report that, shortly after treatment, some cancer cells are sequestered in a quiescent state with low KRAS activity, whereas others bypass this effect to resume proliferation. This rapid divergent response occurs because some quiescent cells produce new KRAS(G12C) in response to suppressed mitogen-activated protein kinase output. New KRAS(G12C) is maintained in its active, drug-insensitive state by epidermal growth factor receptor and aurora kinase signalling. Cells without these adaptive changes-or cells in which these changes are pharmacologically inhibited-remain sensitive to drug treatment, because new KRAS(G12C) is either not available or exists in its inactive, drug-sensitive state. The direct targeting of KRAS oncoproteins has been a longstanding objective in precision oncology. Our study uncovers a flexible non-uniform fitness mechanism that enables groups of cells within a population to rapidly bypass the effect of treatment. This adaptive process must be overcome if we are to achieve complete and durable responses in the clinic.