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Ref Type Journal Article
PMID (33795352)
Authors Schubert L, Le AT, Estrada-Bernal A, Doak AE, Yoo M, Ferrara SE, Goodspeed A, Kinose F, Rix U, Tan AC, Doebele RC
Title Novel Human-Derived RET Fusion NSCLC Cell Lines Have Heterogeneous Responses to RET Inhibitors and Differential Regulation of Downstream Signaling.
Journal Vol Issue Date Pages Journal Short Title
Molecular pharmacology 99 6 2021 Jun 435-447 Mol Pharmacol
URL
Abstract Text Rearranged during transfection ( RET ) rearrangements occur in 1% to 2% of lung adenocarcinomas as well as other malignancies and are now established targets for tyrosine kinase inhibitors. We developed three novel RET fusion-positive ( RET +) patient-derived cancer cell lines, CUTO22 [kinesin 5B ( KIF5B )- RET fusion], CUTO32 ( KIF5B - RET fusion), and CUTO42 (echinoderm microtubule-associated protein-like 4- RET fusion), to study RET signaling and response to therapy. We confirmed each of our cell lines expresses the RET fusion protein and assessed their sensitivity to RET inhibitors. We found that the CUTO22 and CUTO42 cell lines were sensitive to multiple RET inhibitors, whereas the CUTO32 cell line was >10-fold more resistant to three RET inhibitors. We discovered that our RET + cell lines had differential regulation of the mitogen-activated protein kinase and phosphoinositide 3-kinase/protein kinase B (AKT) pathways. After inhibition of RET, the CUTO42 cells had robust inhibition of phosphorylated AKT (pAKT), whereas CUTO22 and CUTO32 cells had sustained AKT activation. Next, we performed a drug screen, which revealed that the CUTO32 cells were sensitive (<1 nM IC 50 ) to inhibition of two cell cycle-regulating proteins, polo-like kinase 1 and Aurora kinase A. Finally, we show that two of these cell lines, CUTO32 and CUTO42, successfully establish xenografted tumors in nude mice. We demonstrated that the RET inhibitor BLU-667 was effective at inhibiting tumor growth in CUTO42 tumors but had a much less profound effect in CUTO32 tumors, consistent with our in vitro experiments. These data highlight the utility of new RET+ models to elucidate differences in response to tyrosine kinase inhibitors and downstream signaling regulation. Our RET+ cell lines effectively recapitulate the interpatient heterogeneity observed in response to RET inhibitors and reveal opportunities for alternative or combination therapies. SIGNIFICANCE STATEMENT: We have derived and characterized three novel rearranged during transfection (RET) fusion non-small cell lung cancer cell lines and demonstrated that they have differential responses to RET inhibition as well as regulation of downstream signaling, an area that has previously been limited by a lack of diverse cell line modes with endogenous RET fusions. These data offer important insight into regulation of response to RET tyrosine kinase inhibitors and other potential therapeutic targets.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
EML4 - RET lung adenocarcinoma conflicting Trametinib Preclinical - Cell line xenograft Actionable In a preclinical study, a patient-derived lung adenocarcinoma cell line harboring EML4-RET was resistant to treatment with Mekinist (trametinib), demonstrating decreased cell proliferation in culture, but led to delayed tumor growth in a cell line xenograft model (PMID: 33795352). 33795352
EML4 - RET lung adenocarcinoma predicted - sensitive Volasertib Preclinical - Patient cell culture Actionable In a preclinical study, a patient-derived lung adenocarcinoma cell line harboring EML4-RET was moderately sensitive to treatment with Volasertib (BI 6727) in culture (PMID: 33795352). 33795352
EML4 - RET lung adenocarcinoma sensitive RXDX-105 Preclinical - Patient cell culture Actionable In a preclinical study, a patient-derived lung adenocarcinoma cell line harboring EML4-RET was sensitive to treatment with Agerafenib (RXDX-105) in culture, demonstrating decreased Akt phosphorylation and induction of apoptosis (PMID: 33795352). 33795352
EML4 - RET lung adenocarcinoma sensitive Pralsetinib Preclinical - Cell line xenograft Actionable In a preclinical study, a patient-derived lung adenocarcinoma cell line harboring EML4-RET was sensitive to treatment with Gavreto (pralsetinib), demonstrating decreased cell proliferation in culture, and inhibition of tumor growth in a xenograft model (PMID: 33795352). 33795352
EML4 - RET lung adenocarcinoma predicted - sensitive GSK2126458 + RXDX-105 Preclinical - Patient cell culture Actionable In a preclinical study, the addition of Omipalisib (GSK2126458) resulted in increased sensitivity to Agerafenib (RXDX-105) treatment in a patient-derived lung adenocarcinoma cell line harboring EML4-RET in culture (PMID: 33795352). 33795352
EML4 - RET lung adenocarcinoma no benefit RXDX-105 + Trametinib Preclinical - Patient cell culture Actionable In a preclinical study, the addition of Mekinist (trametinib) did not increase sensitivity to Agerafenib (RXDX-105) treatment in a patient-derived lung adenocarcinoma cell line harboring EML4-RET in culture (PMID: 33795352). 33795352
EML4 - RET lung adenocarcinoma predicted - sensitive Ponatinib Preclinical - Patient cell culture Actionable In a preclinical study, Iclusig (ponatinib) treatment induced apoptosis in a patient-derived lung adenocarcinoma cell line harboring EML4-RET in culture (PMID: 33795352). 33795352