Dataset Information

Targeting ST8SIA6-AS1 counteracts KRAS^G12C inhibitor resistance through abolishing the reciprocal activation of PLK1/c-Myc signaling.

ABSTRACT:

Background

KRAS^G12C inhibitors (KRAS^G12Ci) AMG510 and MRTX849 have shown promising efficacy in clinical trials and been approved for the treatment of KRAS^G12C-mutant cancers. However, the emergence of therapy-related drug resistance limits their long-term potential. This study aimed to identify the critical mediators and develop overcoming strategies.

Methods

By using RNA sequencing, RT-qPCR and immunoblotting, we identified and validated the upregulation of c-Myc activity and the amplification of the long noncoding RNA ST8SIA6-AS1 in KRAS^G12Ci-resistant cells. The regulatory axis ST8SIA6-AS1/Polo-like kinase 1 (PLK1)/c-Myc was investigated by bioinformatics, RNA fluorescence in situ hybridization, RNA immunoprecipitation, RNA pull-down and chromatin immunoprecipitation. Gain/loss-of-function assays, cell viability assay, xenograft models, and IHC staining were conducted to evaluate the anti-cancer effects of co-inhibition of ST8SIA6-AS1/PLK1 pathway and KRAS both in vitro and in vivo.

Results

KRAS^G12Ci sustainably decreased c-Myc levels in responsive cell lines but not in cell lines with intrinsic or acquired resistance to KRAS^G12Ci. PLK1 activation contributed to this ERK-independent c-Myc stability, which in turn directly induced PLK1 transcription, forming a positive feedback loop and conferring resistance to KRAS^G12Ci. ST8SIA6-AS1 was found significantly upregulated in resistant cells and facilitated the proliferation of KRAS^G12C-mutant cancers. ST8SIA6-AS1 bound to Aurora kinase A (Aurora A)/PLK1 and promoted Aurora A-mediated PLK1 phosphorylation. Concurrent targeting of KRAS and ST8SIA6-AS1/PLK1 signaling suppressed both ERK-dependent and -independent c-Myc expression, synergistically led to cell death and tumor regression and overcame KRAS^G12Ci resistance.

Conclusions

Our study deciphers that the axis of ST8SIA6-AS1/PLK1/c-Myc confers both intrinsic and acquired resistance to KRAS^G12Ci and represents a promising therapeutic target for combination strategies with KRAS^G12Ci in the treatment of KRAS^G12C-mutant cancers.

SUBMITTER: Wang Y

PROVIDER: S-EPMC10724920 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Publications

Targeting ST8SIA6-AS1 counteracts KRAS<sup>G12C</sup> inhibitor resistance through abolishing the reciprocal activation of PLK1/c-Myc signaling.

Wang Yafang Y Yao Mingyue M Li Cheng C Yang Kexin K Qin Xiaolong X Xu Lansong L Shi Shangxuan S Yu Chengcheng C Meng Xiangjun X Xie Chengying C

Experimental hematology & oncology 20231216 1

<h4>Background</h4>KRAS<sup>G12C</sup> inhibitors (KRAS<sup>G12C</sup>i) AMG510 and MRTX849 have shown promising efficacy in clinical trials and been approved for the treatment of KRAS<sup>G12C</sup>-mutant cancers. However, the emergence of therapy-related drug resistance limits their long-term potential. This study aimed to identify the critical mediators and develop overcoming strategies.<h4>Methods</h4>By using RNA sequencing, RT-qPCR and immunoblotting, we identified and validated the upreg ...[more]

PMID: 38104151

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Project description:BackgroundNo therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRASG12C.MethodsWe conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.ResultsA total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma.ConclusionsSotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).

Dataset Information

Targeting ST8SIA6-AS1 counteracts KRAS^G12C inhibitor resistance through abolishing the reciprocal activation of PLK1/c-Myc signaling.

Background

Methods

Results

Conclusions

Publications

Targeting ST8SIA6-AS1 counteracts KRAS<sup>G12C</sup> inhibitor resistance through abolishing the reciprocal activation of PLK1/c-Myc signaling.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Targeting ST8SIA6-AS1 counteracts KRASG12C inhibitor resistance through abolishing the reciprocal activation of PLK1/c-Myc signaling.

Background

Methods

Results

Conclusions

Publications

Targeting ST8SIA6-AS1 counteracts KRAS<sup>G12C</sup> inhibitor resistance through abolishing the reciprocal activation of PLK1/c-Myc signaling.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Targeting ST8SIA6-AS1 counteracts KRAS^G12C inhibitor resistance through abolishing the reciprocal activation of PLK1/c-Myc signaling.