Oncogenic fusion events have been identified in a broad range of tumors. Among them, RET rearrangements represent distinct and potentially druggable targets that are recurrently found in lung adenocarcinomas. Here, we provide further evidence that current anti-RET drugs may not be potent enough to induce durable responses in such tumors. We report that potent inhibitors such as AD80 or ponatinib that stably bind in the DFG-out conformation of RET may overcome these limitations and selectively kill RET-rearranged tumors. Using chemical genomics in conjunction with phosphoproteomic analyses in RET-rearranged cells we identify the CCDC6-RETI788N mutation and drug-induced MAPK pathway reactivation as possible mechanisms, by which tumors may escape the activity of RET inhibitors. Our data provide mechanistic insight into the druggability of RET kinase fusions that may be of help for the development of effective therapies targeting such tumors.
Purpose: The 8p12-p11 locus is frequently amplified in squamous cell lung cancer (SQLC); the receptor tyrosine kinase fibroblast growth factor receptor 1 (FGFR1) being one of the most prominent targets of this amplification. Thus, small molecules inhibiting FGFRs have been employed to treat FGFR1-amplified SQLC. However, only about 11% of such FGFR1-amplified tumors respond to single-agent FGFR inhibition and several tumors exhibited insufficient tumor shrinkage, compatible with the existence of drug-resistant tumor cells.Experimental Design: To investigate possible mechanisms of resistance to FGFR inhibition, we studied the lung cancer cell lines DMS114 and H1581. Both cell lines are highly sensitive to three different FGFR inhibitors, but exhibit sustained residual cellular viability under treatment, indicating a subpopulation of existing drug-resistant cells. We isolated these subpopulations by treating the cells with constant high doses of FGFR inhibitors.Results: The FGFR inhibitor-resistant cells were cross-resistant and characterized by sustained MAPK pathway activation. In drug-resistant H1581 cells, we identified NRAS amplification and DUSP6 deletion, leading to MAPK pathway reactivation. Furthermore, we detected subclonal NRAS amplifications in 3 of 20 (15%) primary human FGFR1-amplified SQLC specimens. In contrast, drug-resistant DMS114 cells exhibited transcriptional upregulation of MET that drove MAPK pathway reactivation. As a consequence, we demonstrate that rational combination therapies resensitize resistant cells to treatment with FGFR inhibitors.Conclusions: We provide evidence for the existence of diverse mechanisms of primary drug resistance in FGFR1-amplified lung cancer and provide a rational strategy to improve FGFR inhibitor therapies by combination treatment.
1 LPS-NOS). Libraries were prepared using a custom panel covering 31 MZL-associated genes (Qiagen Hilden, Germany) and sequenced with NextSeq (Illumina, San Diego CA). Results:We found mutations in 77% of the tissue-based samples (88% SMZL, 59% EMZL, 100% NMZL, 69% MZ-CBL and 91% LPS-NOS). The most frequently mutated genes in SMZL were KLF2 (27%), DNMT3A (24%), TP53 (21%), TNFAIP3 (18%), KMT2D (18%), ARID1A (18%), CCND3 (12%) and MYD88 (12%); in EMZL TNFAIP3 (19%), TET2 (19%) and KMT2D (9%); in NMZL KMT2D stood outand TP53 (13%); in LPS-NOS TP53 (36%), MYD88 (27%), CCND3 (18%) and BIRC3 (18%) (Figure 1). KLF2 was overrepresented in SMZL (p < 0.05) and TP53 was underrepresented in EZML (p < 0.05) compared to the other MZL types. Overall, 14/98 patients were TP53mut (8/14 multi-hit, 7 with cooccurrence of 17p deletion and 1 with 3 mutations). When comparing SMZL and MZ-CBL, KLF2 mutations defined SMZL over MZ-CBL (9/33 vs. 0/16, p < 0.05). The ability to find any tissue mutation in cfDNA was 94% in SMZL, 33% in EMZL, 100% in NMZL and 100% in MZ-CBL. Besides, in 76% of SMZL we detected the 100% of the tissue mutations. cfDNA revealed mutations not present in the tissue in 41% of SMZL, 33% of MALT, 100% of NMZL and 0% of MZ-CBL (86%, 50% and 50% of these mutations respectively were found in clonal hematopoiesis (CH) potentially related genes: DNMT3A, TET2, ASXL1 and TP53).Conclusions: NGS allows the molecular characterization of patients with MZL. MZ-CBL share a similar genetic profile to SMZL but with lower KLF2 mutations. TP53 involvement (in many cases multi-hit) seems frequent in MZL except for EMZL. cfDNA is a useful tool for the genetic characterization of MZL where apart from detecting tissue mutations we can identify additional mutations and CH not visible in the tissue.
<p>Supplementary Figure 1 Short Tandem Repeat Analysis for H1581 and DMS114 Cells; Supplementary Figure 2 Genomic Alteration Validation of NRAS and DUSP6; Supplementary Figure 3 Genomic Differences in DMS114 and DMS114_BGJp Cells; Supplementary Figure 4 Transcriptional Change of DMS114 and DMS114_BGJr; Supplementary Figure 5 Analysis of a Patient with a Relapse under BGJ398</p>
<div>Abstract<p><b>Purpose:</b> The 8p12-p11 locus is frequently amplified in squamous cell lung cancer (SQLC); the receptor tyrosine kinase fibroblast growth factor receptor 1 (FGFR1) being one of the most prominent targets of this amplification. Thus, small molecules inhibiting FGFRs have been employed to treat <i>FGFR1</i>-amplified SQLC. However, only about 11% of such <i>FGFR1</i>-amplified tumors respond to single-agent FGFR inhibition and several tumors exhibited insufficient tumor shrinkage, compatible with the existence of drug-resistant tumor cells.</p><p><b>Experimental Design:</b> To investigate possible mechanisms of resistance to FGFR inhibition, we studied the lung cancer cell lines DMS114 and H1581. Both cell lines are highly sensitive to three different FGFR inhibitors, but exhibit sustained residual cellular viability under treatment, indicating a subpopulation of existing drug-resistant cells. We isolated these subpopulations by treating the cells with constant high doses of FGFR inhibitors.</p><p><b>Results:</b> The FGFR inhibitor–resistant cells were cross-resistant and characterized by sustained MAPK pathway activation. In drug-resistant H1581 cells, we identified <i>NRAS</i> amplification and <i>DUSP6</i> deletion, leading to MAPK pathway reactivation. Furthermore, we detected subclonal <i>NRAS</i> amplifications in 3 of 20 (15%) primary human <i>FGFR1</i>-amplified SQLC specimens. In contrast, drug-resistant DMS114 cells exhibited transcriptional upregulation of <i>MET</i> that drove MAPK pathway reactivation. As a consequence, we demonstrate that rational combination therapies resensitize resistant cells to treatment with FGFR inhibitors.</p><p><b>Conclusions:</b> We provide evidence for the existence of diverse mechanisms of primary drug resistance in <i>FGFR1</i>-amplified lung cancer and provide a rational strategy to improve FGFR inhibitor therapies by combination treatment. <i>Clin Cancer Res; 23(18); 5527–36. ©2017 AACR</i>.</p></div>
<div>Abstract<p><b>Purpose:</b> The 8p12-p11 locus is frequently amplified in squamous cell lung cancer (SQLC); the receptor tyrosine kinase fibroblast growth factor receptor 1 (FGFR1) being one of the most prominent targets of this amplification. Thus, small molecules inhibiting FGFRs have been employed to treat <i>FGFR1</i>-amplified SQLC. However, only about 11% of such <i>FGFR1</i>-amplified tumors respond to single-agent FGFR inhibition and several tumors exhibited insufficient tumor shrinkage, compatible with the existence of drug-resistant tumor cells.</p><p><b>Experimental Design:</b> To investigate possible mechanisms of resistance to FGFR inhibition, we studied the lung cancer cell lines DMS114 and H1581. Both cell lines are highly sensitive to three different FGFR inhibitors, but exhibit sustained residual cellular viability under treatment, indicating a subpopulation of existing drug-resistant cells. We isolated these subpopulations by treating the cells with constant high doses of FGFR inhibitors.</p><p><b>Results:</b> The FGFR inhibitor–resistant cells were cross-resistant and characterized by sustained MAPK pathway activation. In drug-resistant H1581 cells, we identified <i>NRAS</i> amplification and <i>DUSP6</i> deletion, leading to MAPK pathway reactivation. Furthermore, we detected subclonal <i>NRAS</i> amplifications in 3 of 20 (15%) primary human <i>FGFR1</i>-amplified SQLC specimens. In contrast, drug-resistant DMS114 cells exhibited transcriptional upregulation of <i>MET</i> that drove MAPK pathway reactivation. As a consequence, we demonstrate that rational combination therapies resensitize resistant cells to treatment with FGFR inhibitors.</p><p><b>Conclusions:</b> We provide evidence for the existence of diverse mechanisms of primary drug resistance in <i>FGFR1</i>-amplified lung cancer and provide a rational strategy to improve FGFR inhibitor therapies by combination treatment. <i>Clin Cancer Res; 23(18); 5527–36. ©2017 AACR</i>.</p></div>
<p>Supplementary Figure 1 Short Tandem Repeat Analysis for H1581 and DMS114 Cells; Supplementary Figure 2 Genomic Alteration Validation of NRAS and DUSP6; Supplementary Figure 3 Genomic Differences in DMS114 and DMS114_BGJp Cells; Supplementary Figure 4 Transcriptional Change of DMS114 and DMS114_BGJr; Supplementary Figure 5 Analysis of a Patient with a Relapse under BGJ398</p>
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