JAK2 inhibition sensitizes resistant EGFR-mutant lung adenocarcinoma to tyrosine kinase inhibitors

Gao, Sizhi Paul; Chang, Qing; Mao, Ninghui; Daly, Laura; Vogel, Robert; Chan, Tyler; Liu, Shu Hui; Bournazou, Eirini; Schori, Erez; Zhang, Haiying; Brewer, Monica Red; Pao, William; Morris, Luc G.T.; Ladanyi, Marc; Arcila, Maria E.; Manova‐Todorova, Katia; Stanchina, Elisa de; Norton, Larry; Levine, Ross L.; Altan‐Bonnet, Grégoire; Solit, David B.; Zinda, Michael; Huszar, Dennis; Lyden, David; Bromberg, Jacqueline

doi:10.1126/scisignal.aac8460

Cited by 55 publications

(47 citation statements)

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“…Specifically, it has been described that JAK-STAT pathway activity was upregulated in EGFR TKI resistant, EGFR mutant NSCLC cells, and JAK2 inhibition re-sensitizes resistant cells to EGFR TKIs [56,57]. A recent study also delineated JAK-STAT pathway as a key mediator in lung cancer metastasis [58].…”

Section: Discussionmentioning

confidence: 99%

Cancer gene profiling in non-small cell lung cancers reveals activating mutations in JAK2 and JAK3 with therapeutic implications

et al. 2017

Genome Med

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Section: Discussionmentioning

confidence: 99%

Cancer gene profiling in non-small cell lung cancers reveals activating mutations in JAK2 and JAK3 with therapeutic implications

et al. 2017

Genome Med

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“…17 We hypothesized that EGFR expression on exosomes might recapitulate what was observed in cell lines. We examined EGFR levels from H1975 (erlotinib resistant) cells and exosomes following treatment with combination JAK1/2 inhibitor and erlotinib.…”

Section: Resultsmentioning

confidence: 97%

“…These exploratory observations suggest that exosomal EGFR levels reflect the effects of combined ruxolitinib and erlotinib on tumor EGFR expression, which are predicted to decline based on our pre-clinical data. 17 …”

Section: Resultsmentioning

confidence: 99%

“…pSTAT3 is present in nearly all EGFR -mutant lung cancers cells, with two thirds of EGFR -mutant tumors with acquired resistance to erlotinib having high expression of pSTAT3. 16, 17 EGFR activation results in downstream STAT3 activation in a JAK-dependent manner, presumably through FGFR and IL-6 signaling. 16, 18 Treatment of EGFR -mutant cell lines with erlotinib dramatically increased pSTAT3, while knockdown of STAT3 by RNAi led to increased apoptosis and enhanced erlotinib sensitivity.…”

Section: Introductionmentioning

confidence: 99%

“…Mechanistically, JAK2 inhibition uncoupled EGFR from its negative regulators, increasing EGFR abundance and heterodimerization of mutant and wild-type EGFR subunits, the activity of which was then able to be blocked by EGFR TKIs. 17 …”

Section: Introductionmentioning

confidence: 99%

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A Phase 1/2 Trial of Ruxolitinib and Erlotinib in Patients with EGFR -Mutant Lung Adenocarcinomas with Acquired Resistance to Erlotinib

Perez

Chang

et al. 2017

Journal of Thoracic Oncology

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Introduction Patients with EGFR-mutant lung cancers develop resistance to EGFR tyrosine kinase inhibitors. New treatments are needed to address resistance not mediated by EGFR T790M; pre-clinical evidence suggests that the JAK/STAT signaling pathway is important in acquired resistance to EGFR-directed therapy. Methods We evaluated toxicity and efficacy of erlotinib and ruxolitinib in patients with EGFR-mutant lung cancers with acquired resistance to erlotinib. Exosomes were analyzed to assess changes in relevant protein expression on treatment. Results We enrolled 22 patients; 12 patients in the phase 1 and 10 patients in the phase 2 portion. We did not observe any dose-limiting toxicities. The MTD was erlotinib 150mg daily and ruxolitinib 20mg twice daily. The most frequent toxicities (any grade) were anemia, diarrhea, and elevation of liver function tests. One partial response was observed (5%, 95% CI: 0–13%). The median progression-free survival was 2.2 months (95% CI: 1.4–4.1 months). Conclusion This is the first study assessing combination of EGFR and JAK inhibition in patients with EGFR-mutant lung cancers. The combination was well-tolerated but ineffective. Exosomal EGFR levels may reflect changes in tumor EGFR expression in response to therapy.

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Characterization of epidermal growth factor receptor (EGFR) P848L, an unusual EGFR variant present in lung cancer patients, in a murine Ba/F3 model

et al. 2019

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Lung cancer patients with mutations in epidermal growth factor receptor (EGFR) benefit from treatments targeting tyrosine kinase inhibitors (TKIs). However, both intrinsic and acquired resistance of tumors to TKIs are common, and EGFR variants have been identified that are resistant to multiple TKIs. In the present study, we characterized selected EGFR variants previously observed in lung cancer patients and expressed in a murine bone marrow pro‐B Ba/F3 cell model. Among these EGFR variants, we report that an exon 20 deletion/insertion mutation S768insVGH is resistant to erlotinib (a first‐generation TKI), but sensitive to osimertinib (a third‐generation TKI). We also characterized a rare exon 21 germline variant, EGFR P848L, which transformed Ba/F3 cells and conferred resistance to multiple EGFR‐targeting TKIs. Our analysis revealed that P848L (a) does not bind erlotinib; (b) is turned over less rapidly than L858R (a common tumor‐derived EGFR mutation); (c) is not autophosphorylated at Tyr 1045 [the major docking site for Cbl proto‐oncogene (c‐Cbl) binding]; and (d) does not bind c‐Cbl. Using viability assays including 300 clinically relevant targeted compounds, we observed that Ba/F3 cells transduced with EGFR P848L, S768insVGH, or L858R have very different drug‐sensitivity profiles. In particular, EGFR P848L, but not L858R or S768insVGH, was sensitive to multiple Janus kinase 1/2 inhibitors. In contrast, cells driven by L858R, but not by P848L, were sensitive to multikinase MAPK/extracellular‐signal‐regulated kinase (ERK) kinase and ERK inhibitors including EGFR‐specific TKIs. These observations suggest that continued investigation of rare TKI‐resistant EGFR variants is warranted to identify optimal treatments for cancer.

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JAK2 inhibition sensitizes resistant EGFR-mutant lung adenocarcinoma to tyrosine kinase inhibitors

Cited by 55 publications

References 57 publications

Cancer gene profiling in non-small cell lung cancers reveals activating mutations in JAK2 and JAK3 with therapeutic implications

Cancer gene profiling in non-small cell lung cancers reveals activating mutations in JAK2 and JAK3 with therapeutic implications

A Phase 1/2 Trial of Ruxolitinib and Erlotinib in Patients with EGFR -Mutant Lung Adenocarcinomas with Acquired Resistance to Erlotinib

Characterization of epidermal growth factor receptor (EGFR) P848L, an unusual EGFR variant present in lung cancer patients, in a murine Ba/F3 model

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