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JAK2-related pathway induces acquired erlotinib resistance in lung cancer cells harboring an epidermal growth factor receptor-activating mutation.

ABSTRACT: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, such as gefitinib and erlotinib, are effective for non-small cell lung cancer with activating EGFR mutations. However, even in patients with an initial dramatic response to such a drug, acquired resistance develops after 6-12 months. A secondary mutation of T790M in EGFR and amplification of the MET gene account for this resistance; however, the mechanism(s) of approximately 30% of acquired resistance cases remain unknown. We established an erlotinib-resistant lung cancer cell line named PC-9/ER3 that harbors an EGFR mutation after continuously exposing PC-9 cells to erlotinib. PC-9/ER3 cells were 136-fold more resistant to erlotinib than the parental cells. Although the PC-9/ER3 cells did not carry the T790M mutation or MET amplification and had similar levels of phosphorylated (p) STAT3, pJAK2 increased in the resistant cells. It was found in the present study that 3-12 h of exposure to erlotinib in both cell lines did not affect pJAK2 expression, but did result in increased pSTAT3 expression. pAkt in PC-9/ER3 cells was less suppressed than in PC-9 cells, although pEGFR and pMAPK were markedly suppressed in both cell lines. The combined treatment of erlotinib plus a JAK2 inhibitor (JSI-124) suppressed pAkt in PC-9/ER3 cells. Similarly, the combination of erlotinib plus JSI-124 or siRNA against JAK2 restored sensitivity to erlotinib in PC-9/ER3 cells. The combination of erlotinib plus JSI-124 was also effective for reducing PC-9/ER3 tumors in a murine xenograft model. Our results suggest that the activation of JAK2 partially accounts for acquired erlotinib resistance.

SUBMITTER: Harada D

PROVIDER: S-EPMC7659254 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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JAK2-related pathway induces acquired erlotinib resistance in lung cancer cells harboring an epidermal growth factor receptor-activating mutation.

Harada Daijiro D Takigawa Nagio N Ochi Nobuaki N Ninomiya Takashi T Yasugi Masayuki M Kubo Toshio T Takeda Hiromasa H Ichihara Eiki E Ohashi Kadoaki K Takata Saburo S Tanimoto Mitsune M Kiura Katsuyuki K

Cancer science 20120724 10

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, such as gefitinib and erlotinib, are effective for non-small cell lung cancer with activating EGFR mutations. However, even in patients with an initial dramatic response to such a drug, acquired resistance develops after 6-12 months. A secondary mutation of T790M in EGFR and amplification of the MET gene account for this resistance; however, the mechanism(s) of approximately 30% of acquired resistance cases remain unknown. We es ...[more]

PMID: 22712764

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Project description:Patients with non-small cell lung cancer (NSCLC) harboring ROS proto-oncogene 1, receptor tyrosine kinase gene (ROS1) chromosomal rearrangements benefit from treatment with the ROS1 inhibitor crizotinib. Limited data exist on the spectrum of resistance mechanisms in ROS1-positive NSCLC. To delineate mechanisms of acquired resistance, we analyzed biopsy samples of tumor lesions that progressed while patients were receiving crizotinib.An activating mutation in the KIT proto-oncogene receptor tyrosine kinase (KIT) (p.D816G) was identified by SNaPshot sequencing in a tumor sample from a patient with ROS1-positive NSCLC identified by fluorescence in situ hybridization whose disease progressed after initial response to crizotinib. In vitro studies included evaluation of KIT mRNA expression by quantitative reverse-transcriptase polymerase chain reactions, transduction of Ba/F3 cells and NSCLC cell lines with KIT-expressing lentiviral plasmids, immunoblotting, and cellular proliferation assays.KIT(D816G) is an activating mutation that induces autophosphorylation and cell proliferation. Expression of the mutant KIT(D816G) receptor in ROS1-positive NSCLC cell lines led to constitutively activated KIT as measured by phosphorylation of the KIT receptor. Expression of the KIT(D816G) rendered the HCC78 and CUTO2 cell lines resistant to crizotinib, and only dual inhibition of ROS1 and KIT with crizotinib and ponatinib could resensitize the cells to inhibition of proliferation. The oncogenic switch observed in ROS1-positive cell lines was not immediate and required pharmacologic inactivation of ROS1.Activation of KIT by a gain-of-function somatic mutation is a novel mechanism of resistance to crizotinib in ROS1-rearranged NSCLC. This bypass signaling pathway serves as a ROS1-independent mechanism of resistance, similarly to previously identified epidermal growth factor receptor or Kirsten rat sarcoma viral oncogene homolog/neuroblastoma RAS viral oncogene homolog signaling pathways, and can potentially be targeted by KIT inhibitors.

Dataset Information

JAK2-related pathway induces acquired erlotinib resistance in lung cancer cells harboring an epidermal growth factor receptor-activating mutation.

Publications

JAK2-related pathway induces acquired erlotinib resistance in lung cancer cells harboring an epidermal growth factor receptor-activating mutation.

Similar Datasets

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