Trp53R172H and kmsg12d cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice

Cancer is the leading cause of death worldwide, and its treatment and outcomes have been dramatically revolutionised by targeted therapies. As the most frequently mutated oncogene, Kirsten rat sarcoma viral oncogene homologue (KRAS) has attracted substantial attention. The understanding of KRAS is constantly being updated by numerous studies on KRAS in the initiation and progression of cancer diseases. However, KRAS has been deemed a challenging therapeutic target, even "undruggable", after drug-targeting efforts over the past four decades. Recently, there have been surprising advances in directly targeted drugs for KRAS, especially in KRAS (G12C) inhibitors, such as AMG510 (sotorasib) and MRTX849 (adagrasib), which have obtained encouraging results in clinical trials. Excitingly, AMG510 was the first drug-targeting KRAS (G12C) to be approved for clinical use this year. This review summarises the most recent understanding of fundamental aspects of KRAS, the relationship between the KRAS mutations and tumour immune evasion, and new progress in targeting KRAS, particularly KRAS (G12C). Moreover, the possible mechanisms of resistance to KRAS (G12C) inhibitors and possible combination therapies are summarised, with a view to providing the best regimen for individualised treatment with KRAS (G12C) inhibitors and achieving truly precise treatment.

KRAS mutation: from undruggable to druggable in cancer

RAS genes are the most commonly mutated oncogenes in cancer, but effective therapeutic strategies to target RAS-mutant cancers have proved elusive. A key aspect of this challenge is the fact that direct inhibition of RAS proteins has proved difficult, leading researchers to test numerous alternative strategies aimed at exploiting RAS-related vulnerabilities or targeting RAS effectors. In the past few years, we have witnessed renewed efforts to target RAS directly, with several promising strategies being tested in clinical trials at different stages of completion. Important advances have also been made in approaches designed to indirectly target RAS by improving inhibition of RAS effectors, exploiting synthetic lethal interactions or metabolic dependencies, using therapeutic combination strategies or harnessing the immune system. In this Review, we describe historical and ongoing efforts to target RAS-mutant cancers and outline the current therapeutic landscape in the collective quest to overcome the effects of this crucial oncogene.

Therapeutic strategies to target RAS-mutant cancers.

Purpose: KRAS-mutant lung cancers have been recalcitrant to treatments including those targeting the MAPK pathway. Covalent inhibitors of KRAS p.G12C allele allow for direct and specific inhibition of mutant KRAS in cancer cells. However, as for other targeted therapies, the therapeutic potential of these inhibitors can be impaired by intrinsic resistance mechanisms. Therefore, combination strategies are likely needed to improve efficacy. Experimental Design: To identify strategies to maximally leverage direct KRAS inhibition we defined the response of a panel of NSCLC models bearing the KRAS G12C–activating mutation in vitro and in vivo. We used a second-generation KRAS G12C inhibitor, ARS1620 with improved bioavailability over the first generation. We analyzed KRAS downstream effectors signaling to identify mechanisms underlying differential response. To identify candidate combination strategies, we performed a high-throughput drug screening across 112 drugs in combination with ARS1620. We validated the top hits in vitro and in vivo including patient-derived xenograft models. Results: Response to direct KRAS G12C inhibition was heterogeneous across models. Adaptive resistance mechanisms involving reactivation of MAPK pathway and failure to induce PI3K–AKT pathway inactivation were identified as likely resistance events. We identified several model-specific effective combinations as well as a broad-sensitizing effect of PI3K-AKT–mTOR pathway inhibitors. The G12Ci+PI3Ki combination was effective in vitro and in vivo on models resistant to single-agent ARS1620 including patient-derived xenografts models. Conclusions: Our findings suggest that signaling adaptation can in some instances limit the efficacy of ARS1620 but combination with PI3K inhibitors can overcome this resistance.

https://clincancerres.aacrjournals.org/content/clincanres/25/2/796.full.pdf

KRAS G12C NSCLC Models Are Sensitive to Direct Targeting of KRAS in Combination with PI3K Inhibition.

Our understanding of how the RAS protein family, and in particular mutant KRAS, promotes metabolic dysregulation in cancer cells has advanced substantially over the last decade. In this Review, we discuss the metabolic reprogramming mediated by oncogenic RAS in cancer and elucidate the underlying mechanisms that could translate to novel therapeutic opportunities to target metabolic vulnerabilities in RAS-driven cancers. Mukhopadhyay, Vander Heiden and McCormick review the metabolic landscape of RAS-driven cancers, the effects of RAS-directed metabolic reprogramming and opportunities for targeting these cancers therapeutically.

The metabolic landscape of RAS-driven cancers from biology to therapy

Activating mutations in the proto-oncogene KRAS are a hallmark of pancreatic ductal adenocarcinoma (PDAC), an aggressive malignancy with few effective therapeutic options. Despite efforts to develop KRAS-targeted drugs, the absolute dependence of PDAC cells on KRAS remains incompletely understood. Here we model complete KRAS inhibition using CRISPR/Cas-mediated genome editing and demonstrate that KRAS is dispensable in a subset of human and mouse PDAC cells. Remarkably, nearly all KRAS deficient cells exhibit phosphoinositide 3-kinase (PI3K)-dependent mitogen-activated protein kinase (MAPK) signaling and induced sensitivity to PI3K inhibitors. Furthermore, comparison of gene expression profiles of PDAC cells retaining or lacking KRAS reveal a role of KRAS in the suppression of metastasis-related genes. Collectively, these data underscore the potential for PDAC resistance to even the very best KRAS inhibitors and provide insights into mechanisms of response and resistance to KRAS inhibition.

/pdf/survival-of-pancreatic-cancer-cells-lacking-kras-function-105v24ojdn.pdf

Survival of pancreatic cancer cells lacking KRAS function

Thermally insulating Bi6B10+2xO24+3x (x =  − 2, − 1,0,1,2) ceramics with neutron/gamma shielding capability

New Design of Bismuth Borate Ceramic/Epoxy Composites with Excellent Fracture Toughness and Radiation Shielding Capabilities

Fabrication of novel BPO4 ceramic foams using the combination of the direct foaming method and freeze‐drying techniques

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Survival of pancreatic cancer cells lacking KRAS function

Survival of pancreatic cancer cells lacking KRAS function

Thermally insulating Bi6B10+2xO24+3x (x = − 2, − 1,0,1,2) ceramics with neutron/gamma shielding capability

New Design of Bismuth Borate Ceramic/Epoxy Composites with Excellent Fracture Toughness and Radiation Shielding Capabilities

Fabrication of novel BPO4 ceramic foams using the combination of the direct foaming method and freeze‐drying techniques