Dataset Information

PAK and PI3K pathway activation confers resistance to KRAS^G12C inhibitor sotorasib.

ABSTRACT:

Background

KRAS is a frequently mutated oncogene in human cancer. Clinical studies on the covalent inhibitors of the KRAS^G12C mutant have reported promising results. However, primary and acquired resistance may limit their clinical use.

Methods

Sotorasib-resistant cell lines were established. We explored the signalling pathways activated in these resistant cell lines and their roles in sotorasib resistance.

Results

The resistant cells exhibited increased cell-matrix adhesion with increased levels of stress fibres and focal adherens. p21-activated kinases (PAKs) were activated in resistant cells, which phosphorylate MEK at serine 298 of MEK and serine 338 of c-Raf to activate the mitogen-activated protein kinase pathway. The PAK inhibitors FRAX597 and FRAX486 in synergy with sotorasib reduced the viability of KRAS^G12C mutant cancer cells. Furthermore, the PI3K/AKT pathway was constitutively active in sotorasib-resistant cells. The overexpression of constitutively activated PI3K or the knockdown of PTEN resulted in resistance to sotorasib. PI3K inhibitor alpelisib was synergistic with sotorasib in compromising the viability of KRAS^G12C mutant cancer cells. Moreover, PI3K and PAK pathways formed a mutual positive regulatory loop that mediated sotorasib resistance.

Conclusions

Our results indicate that the cell-matrix interaction-dependent activation of PAK mediates resistance to sotorasib through the activation of MAPK and PI3K pathways.

SUBMITTER: Chan CH

PROVIDER: S-EPMC9814377 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Publications

PAK and PI3K pathway activation confers resistance to KRAS<sup>G12C</sup> inhibitor sotorasib.

Chan Chien-Hui CH Chiou Li-Wen LW Lee Tsai-Yu TY Liu Yun-Ru YR Hsieh Tsung-Han TH Yang Ching-Yao CY Jeng Yung-Ming YM

British journal of cancer 20221101 1

<h4>Background</h4>KRAS is a frequently mutated oncogene in human cancer. Clinical studies on the covalent inhibitors of the KRAS<sup>G12C</sup> mutant have reported promising results. However, primary and acquired resistance may limit their clinical use.<h4>Methods</h4>Sotorasib-resistant cell lines were established. We explored the signalling pathways activated in these resistant cell lines and their roles in sotorasib resistance.<h4>Results</h4>The resistant cells exhibited increased cell-mat ...[more]

PMID: 36319849

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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.).

Project description:BackgroundSotorasib is the first KRASG12C inhibitor approved by the US Food and Drug Administration for treating KRASG12C-mutant non-small-cell lung cancer (NSCLC). Clinical trials on the therapeutic use of sotorasib for cancer have reported promising results. However, KRASG12C-mutant cancers can acquire resistance to sotorasib after treatment. We incidentally discovered that sotorasib-resistant (SR) cancer cells are addicted to this inhibitor. In this study, we investigated the mechanisms underlying sotorasib addiction.MethodsSotorasib-resistant cells were established using KRASG12C-mutant pancreatic cancer and NSCLC cell lines. Cell viability in the presence or absence of sotorasib and in combination with multiple inhibitors was assessed through proliferation assay and annexin V/propidium iodide (PI) flow cytometry assays. The mechanisms underlying drug addiction were elucidated through 5-bromo-2'-deoxyuridine (BrdU) incorporation assay, immunofluorescence staining, time-lapse microscopy, and comet assay. Furthermore, a subcutaneous xenograft model was used to demonstrate sotorasib addiction in vivo.ResultsIn the absence of sotorasib, the sotorasib-resistant cells underwent p21Waf1/Cip1-mediated cell cycle arrest and caspase-dependent apoptosis. Sotorasib withdrawal resulted in robust activation of mitogen-activated protein kinase (MAPK) pathway, inducing severe DNA damage and replication stress, which activated the DNA damage response (DDR) pathway. Persistent MAPK pathway hyperactivation with DDR exhaustion led to premature mitotic entry and aberrant mitosis, followed by micronucleus and nucleoplasmic bridge formation. Pharmacologic activation of the MAPK pathway with a type I BRAF inhibitor could further enhance the effects of sotorasib withdrawal on sotorasib-resistant cancer cells both in vitro and in vivo.ConclusionsWe elucidated the mechanisms underlying the sotorasib addiction of cancer cells. Sotorasib addiction appears to be mediated through MAPK pathway hyperactivity, DNA damage, replication stress, and mitotic catastrophe. Moreover, we devised a therapeutic strategy involving a type I BRAF inhibitor to strengthen the effects of sotorasib addiction; this strategy may provide clinical benefit for patients with cancer.

Dataset Information

PAK and PI3K pathway activation confers resistance to KRAS^G12C inhibitor sotorasib.

Background

Methods

Results

Conclusions

Publications

PAK and PI3K pathway activation confers resistance to KRAS<sup>G12C</sup> inhibitor sotorasib.

Similar Datasets

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Tweets

Dataset Information

PAK and PI3K pathway activation confers resistance to KRASG12C inhibitor sotorasib.

Background

Methods

Results

Conclusions

Publications

PAK and PI3K pathway activation confers resistance to KRAS<sup>G12C</sup> inhibitor sotorasib.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

PAK and PI3K pathway activation confers resistance to KRAS^G12C inhibitor sotorasib.