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Chemotherapy confers a conserved secondary tolerance to EGFR inhibition via AXL-mediated signaling bypass.

ABSTRACT: Drug resistance remains the major culprit of therapy failure in disseminated cancers. Simultaneous resistance to multiple, chemically different drugs feeds this failure resulting in cancer relapse. Here, we investigate co-resistance signatures shared between antimitotic drugs (AMDs) and inhibitors of receptor tyrosine kinases (RTKs) to probe mechanisms of secondary resistance. We map co-resistance ranks in multiple drug pairs and identified a more widespread occurrence of co-resistance to the EGFR-tyrosine kinase inhibitor (TKI) gefitinib in hundreds of cancer cell lines resistant to at least 11 AMDs. By surveying different parameters of genomic alterations, we find that the two RTKs EGFR and AXL displayed similar alteration and expression signatures. Using acquired paclitaxel and epothilone B resistance as first-line AMD failure models, we show that a stable collateral resistance to gefitinib can be relayed by entering a dynamic, drug-tolerant persister state where AXL acts as bypass signal. Delayed AXL degradation rendered this persistence to become stably resistant. We probed this degradation process using a new EGFR-TKI candidate YD and demonstrated that AXL bypass-driven collateral resistance can be suppressed pharmacologically. The findings emphasize that AXL bypass track is employed by chemoresistant cancer cells upon EGFR inhibition to enter a persister state and evolve resistance to EGFR-TKIs.

SUBMITTER: Aldonza MBD

PROVIDER: S-EPMC8044124 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe bromodomain and extra-terminal domain (BET) inhibitor is a type of anti-tumor agent, currently being evaluated in phase I and II clinical trials for cancer therapy. It can decrease MYC expression levels and cause effective anti-tumor effects in diverse human cancers. However, its cytotoxic effect and related mechanisms of drug resistance are poorly understood in hepatocellular carcinomas (HCC). Here, we investigated the anti-tumor effects of BET inhibitor on HCC and the molecular mechanisms involved in its associated drug resistance.MethodsWe assessed the cytotoxicity of BET inhibitor on HCC cells compared with sorafenib by cell viability assay, metastasis assay and reproduced the anti-tumor effect in xenograft mouse model. In addition, the molecular mechanisms involved in drug resistance on JQ1-resistant HCC cells were revealed by western blotting, qRT-PCR, whole exome-sequencing and gene-editing technology. Finally, with specific inhibition of EGFR or ERK activity by interference RNAs or inhibitors, the efficacy of the synergistic treatment was investigated using cell viability assay, colony formation, apoptosis and xenograft mouse model.ResultsWe found that JQ1, a commonly used BET bromo-domain inhibitor, offered a better anti-tumor response than sorafenib in MYC-positive HCC cells by inducing apoptosis in vitro and in vivo. Unlike sorafenib, JQ1 treatment significantly impaired mitochondrial respiration and glycolysis in HCC cells. Importantly, we revealed that MAPK activation by a previously undescribed activating mutation of EGFR-I645L, was critical for JQ1 sensitivity through stabilizing oncogenic MYC protein in JQ1-resistant HCC cells. Inhibition of either EGFR or ERK activity overcame the JQ1 resistance and significantly decreased MYC protein level in vitro and in vivo.ConclusionSince MYC amplification is frequently identified in HCC, co-occurring with EGFR amplification, our findings suggest that targeting EGFR signaling might be essential for JQ1 therapy in advanced HCC.

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Chemotherapy confers a conserved secondary tolerance to EGFR inhibition via AXL-mediated signaling bypass.

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