Stopping the beating heart of cancer: KRAS reviewed

Herdeis, Lorenz; Gerlach, Daniel; McConnell, Darryl B.; Kessler, Dirk

doi:10.1016/j.sbi.2021.06.013

Cited by 43 publications

(42 citation statements)

References 63 publications

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“…Generally, oncogenic mutations in RAS impair intrinsic and GTPase-activating protein (GAP)stimulated GTP hydrolysis activities (G12 and Q61) and/or cause fast-cycling enhanced nucleotide exchange (G13, Q61, and A146), favoring the persistent formation of active RAS-GTP (Figure 3A) [21]. However, an emerging view is that mutation-distinct consequences on RAS structure, biochemistry, and function occur that can be exploited for the development of mutation-specific therapeutic strategies [9,22,23].…”

Section: Ras Mutations In Cancermentioning

confidence: 99%

“…After nearly four decades of effort, the development of KRAS G12C -specific inhibitors [27][28][29], with one (sotorasib) recently approved for the treatment of KRAS G12C -mutant lung cancer [30], marks a major milestone in RAS research. Inspired by the seminal findings of Shokat and colleagues [29], the development of these inhibitors took advantage of the uniquely reactive nature of the cysteine substitution and the recognition of a previously unrecognized hydrophobic pocket positioned in the switch II (SII; see below) region of KRAS [22]. Sotorasib and other KRAS G12Cspecific inhibitors under clinical evaluation preferentially recognize the inactive GDP-complexed form of KRAS G12C .…”

Section: Ras Mutations In Cancermentioning

confidence: 99%

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RHOA takes the RHOad less traveled to cancer

Schaefer

Der

2022

Trends in Cancer

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Section: Ras Mutations In Cancermentioning

confidence: 99%

Section: Ras Mutations In Cancermentioning

confidence: 99%

RHOA takes the RHOad less traveled to cancer

Schaefer

Der

2022

Trends in Cancer

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“…In the United States alone, nearly 150,000 new cases of KRAS-mutated cancers are diagnosed each year across these three cancer types. More than half of all KRAS-driven cancers are caused by the three most common KRAS alleles, G12D, G12V, and G12C, which account for approximately 100,000 new cases in the US [3].…”

Section: Introductionmentioning

confidence: 99%

Inhibitor of the nuclear transport protein XPO1 enhances the anticancer efficacy of KRAS G12C inhibitors in preclinical models of KRAS G12C mutant cancers

Khan

Nagasaka

et al. 2022

Preprint

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The identification of molecules that can bind covalently to KRAS G12C and lock it in an inactive GDP-bound conformation has opened the door to targeting KRAS G12C selectively. These agents have shown promise in preclinical tumor models and clinical trials. FDA has recently granted approval to sotorasib for KRAS G12C mutated non-small cell lung cancer (NSCLC). However, patients receiving these agents as monotherapy may not respond and generally develop drug resistance over time. This necessitates the development of multi-targeted approaches that can potentially sensitize tumors to KRAS inhibitors. We generated KRAS G12C inhibitor-resistant cell lines and observed that they exhibit sensitivity toward selinexor, a selective inhibitor of nuclear export protein exportin1 (XPO1), as a single agent. KRAS G12C inhibitor MRTX1257 in combination with selinexor suppressed the proliferation of KRAS G12C mutant cancer cell lines MiaPaCa-2 and NCI-H2122 in a synergistic manner. Moreover, combined treatment of selinexor with KRAS G12C inhibitors resulted in enhanced spheroid disintegration, a reduction in the number and size of colonies formed by G12C mutant cancer cells. A combination of selinexor with KRAS G12C inhibitors potentiated the inhibition of KRAS expression in MiaPaCa-2 cells. NF-kB protein expression was also markedly reduced by selinexor and MRTX1257 combination. In an in vivo KRAS G12C cell-derived xenograft model, oral administration of a combination of selinexor and sotorasib was demonstrated to reduce tumor burden and enhance survival. In conclusion, we have shown that the nuclear transport protein XPO1 inhibitor can enhance the anticancer activity of KRAS G12C inhibitors in preclinical cancer models.

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“…Unfortunately, KRAS* has long been considered “undruggable” for a variety of reasons. That status changed very recently with the development of small molecules that specifically target the G12C KRAS* protein, which has shown clinical efficacy ( Herdeis et al 2021 ). However, this specific KRAS mutation is found in only a small fraction (∼1%) of human PDACs compared with G12D (41%), G12V (34%), or G12R (16%) ( Waters and Der 2018 ).…”

mentioning

confidence: 99%

“…However, this specific KRAS mutation is found in only a small fraction (∼1%) of human PDACs compared with G12D (41%), G12V (34%), or G12R (16%) ( Waters and Der 2018 ). Fortunately, small molecules that target some of these more common KRAS mutants are in development ( Herdeis et al 2021 ), giving hope for the future of effective treatment of the vast majority of PDAC patients.…”

mentioning

confidence: 99%

Anticipating resistance to KRAS inhibition: a novel role for USP21 in macropinocytosis regulation

Crawford

2021

Genes Dev.

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Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Virtually all PDAC harbors an oncogenic mutation in the KRAS gene, making it the prime target for therapy. Most previous attempts to inhibit KRAS directly have been disappointing, but recent success in targeting some KRAS mutants presages a new era in PDAC therapy. Models of PDAC have predicted that identifying KRAS inhibitor resistance mechanisms will be critical. In this issue of Genes & Development, Hou and colleagues (pp. 1327–1332) identify one such mechanism in which the deubiquitinase USP21 up-regulates the nutrient-scavenging process of macropinocytosis, rescuing PDAC cells from Kras extinction.

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Stopping the beating heart of cancer: KRAS reviewed

Cited by 43 publications

References 63 publications

RHOA takes the RHOad less traveled to cancer

RHOA takes the RHOad less traveled to cancer

Inhibitor of the nuclear transport protein XPO1 enhances the anticancer efficacy of KRAS G12C inhibitors in preclinical models of KRAS G12C mutant cancers

Anticipating resistance to KRAS inhibition: a novel role for USP21 in macropinocytosis regulation

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