MAPK Pathway Alterations Correlate with Poor Survival and Drive Resistance to Therapy in Patients with Lung Cancers Driven by <i>ROS1</i> Fusions

Sato, Hiroki; Schoenfeld, Adam J.; Siau, Evan; Lu, Yao; Tai, Hui-Chun; Suzawa, Ken; Kubota, Daisuke; Lui, Allan J.W.; Qeriqi, Besnik; Mattar, Marissa S.; Offin, Michael; Sakaguchi, Masakiyo; Toyooka, Shinichi; Drilon, Alexander; Rosen, Neal; Kris, Mark G.; Solit, David B.; Stanchina, Elisa de; Davare, Monika A.; Riely, Gregory J.; Ladanyi, Marc; Somwar, Romel

doi:10.1158/1078-0432.ccr-19-3321

Cited by 41 publications

(41 citation statements)

References 48 publications

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“…In addition, sustained downstream pathway activation was also detected and could be overcome in vitro with combination entrectinib and selumetinib. These data were consistent with other reports that have demonstrated activation of mitogen-activated protein kinase (MAPK) pathway as mediators of innate and acquired resistance for both ROS1 and TRK fusions ( 32 , 33 ). In patients with tumors harboring ROS1 fusions, MAPK upregulation was also associated with worse survival ( 32 ).…”

Section: Discussionsupporting

confidence: 93%

“…These data were consistent with other reports that have demonstrated activation of mitogen-activated protein kinase (MAPK) pathway as mediators of innate and acquired resistance for both ROS1 and TRK fusions ( 32 , 33 ). In patients with tumors harboring ROS1 fusions, MAPK upregulation was also associated with worse survival ( 32 ). In a plasma-based NGS analysis of 18 paired blood samples at baseline and on disease progression on entrectinib from STARTRK-2 trial, acquired on-target ROS1 resistance mutations (G2032R and F2004C/I) were detected in four (28%) patients ( 34 ).…”

Section: Discussionsupporting

confidence: 93%

See 1 more Smart Citation

Cases of ROS1-rearranged lung cancer: when to use crizotinib, entrectinib, lorlatinib, and beyond?

Sehgal¹,

Piper-Vallillo²,

Viray³

et al. 2020

Precis Cancer Med

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ROS1 -rearranged (also known as ROS1 fusion-positive) non-small-cell lung cancer is an uncommon but distinct molecular subgroup seen in approximately 1–2% of cases. Oncogene addiction due to constitutive ROS1 tyrosine kinase activation has allowed development of molecularly targeted therapies with remarkable anti-tumor activity. Both crizotinib and entrectinib, multitargeted tyrosine kinase inhibitors (TKIs) have now received approval by the FDA for treatment of patients with advanced ROS1 -rearranged lung cancers; however, the clinical efficacy and safety of these drugs have been derived from expansion cohorts of single-arm phase I or basket clinical trials with relatively small populations of this clinically and molecularly distinct subgroup. Both drugs lead to high objective response rates (approximately 70–80%) and have manageable side effects, although only entrectinib has potent intracranial efficacy. Lorlatinib is an oral brain-penetrant ALK/ROS1 TKI with activity in both TKI-naïve and some crizotinib-resistant settings (albeit with limited potency against the crizotinib/entrectinib-resistant ROS1 -G2032R mutation). We describe cases of advanced ROS1 -rearranged lung cancer receiving crizotinib, entrectinib, and/or lorlatinib in first and later line treatment settings to dissect the current state of evidence supporting management decisions for these patients. The next generation ROS1 TKIs (repotrectinib and DS-6051b), owing to their broad activity against kinase mutations including ROS1 -G2032R in preclinical studies, hold promise to transform the current treatment paradigm and permit even further gains with regards to long-term outcomes in this subset of patients.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 93%

Cases of ROS1-rearranged lung cancer: when to use crizotinib, entrectinib, lorlatinib, and beyond?

Sehgal¹,

Piper-Vallillo²,

Viray³

et al. 2020

Precis Cancer Med

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“…These include the known ROS1 resistance alterations composed of ROS1 point mutation and the likely ROS1 resistance alterations based on our literature search composed of KIT mutations, EGFR mutations, KRAS mutations/amplifications, NRAS mutations, MAP2K1 mutations and NF1 mutations. [20][21][22][23][24][25] In our NSCLC cohort, we saw that half of the known and likely resistance alterations were ROS1 kinase domain point mutations which can potentially lead to steric interferences with drug binding that causes ROS1 therapy inhibition and were likely acquired post-treatment. 20,24 This contrasts with the non-NSCLC cohort where no ROS1 point mutations was identified, likely due to the lower prevalence of ROS1-TKI treatment in this group.…”

Section: Discussionmentioning

confidence: 97%

“…When examining the 25 genes with the most GA in NSCLC ROS1 fusion pos cases and NSCLC ROS1 fusion neg cases, we KIT mutations, EGFR mutations, KRAS mutations/amplifications, NRAS mutations, MAP2K1 mutations and NF1 mutations. [20][21][22][23][24][25] In NSCLC, the rate of known or likely alterations potentially contributing to resistance to ROS1 tyrosine kinase inhibitors (TKIs) was 7.3% (20/275) (Table S8) For the non-NSCLC cohort, the rate of known or likely alterations potentially contributing to resistance to ROS1 TKIs was 4.9% (4/81) ( Table S9).…”

Section: Mutational Profile In Subsets Of Ros1 Fusion and Ros1 Wildmentioning

confidence: 99%

Clinicopathologic, genomic and protein expression characterization of 356ROS1fusion driven solid tumors cases

Huang¹,

Haberberger²,

Sokol³

et al. 2020

Intl Journal of Cancer

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Based on the approvals of crizotinib and entrectinib by the Food and Drug Administration for the treatment of ROS1 positive nonsmall cell lung cancer (NSCLC), we sought to examine the mutational profile of a variety of solid tumors (excluding sarcomas) with ROS1 fusions that underwent comprehensive genomic profiling. A review of our database was performed to extract all nonsarcoma patients with ROS1 fusions that were discovered by the hybrid capture‐based DNA only sequencing assays. We examined the coalterations representing potentially targetable biomarkers, resistance alterations and other alterations in these cases. In addition, we examined the histologic characteristics and protein expression with immunohistochemistry (IHC). From a series of clinically advanced nonsarcoma solid tumors, 356 unique cases with ROS1 fusions included 275 (77.2%) NSCLC and 81 (22.8%) non‐NSCLC. Ten novel ROS1 fusions were discovered. Importantly, the NSCLC ROS1 fusionpos tumors had a higher PD‐L1 IHC expression positivity when compared to the NSCLC ROS1 fusionneg population (P = .012, Chi‐squared). The frequency of known and likely anti‐ROS1 targeted therapy resistance genomic alterations in NSCLC was 7.3% (20/275) and in non‐NSCLC was 4.9% (4/81). Overall, the coalteration profile of ROS1 fusionpos NSCLC and non‐NSCLC was similar with only three genes altered significantly more frequently in non‐NSCLC vs NSCLC: TERT, PTEN, APC. In our study, we characterized a large cohort of ROS1 fusionpos NSCLC and non‐NSCLC solid tumors and discovered 10 novel ROS1 fusions.

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“…Cells expressing the fusion were selected using 200 mg/mL hygromycin. The HBECp53-SLC3A2-NRG1 cells are an unselected population in which the SLC3A2-NRG1 fusion has been introduced by CRISPR-Cas9-mediated genome editing, as we have described previously for ROS1 and BRAF fusions (20,21). HCC-95 cells were obtained from Dr. William Lockwood (BC Cancer Center, Vancouver, British Columbia, Canada, RRID: CVCL_5137) and these cells were found to have NRG1 amplification by whole-exome sequencing (2).…”

Section: Cell Linesmentioning

confidence: 99%

The Anti-HER3 mAb Seribantumab Effectively Inhibits Growth of Patient-Derived and Isogenic Cell Line and Xenograft Models with Oncogenic NRG1 Fusions

Odintsov

Lui

Sisso

et al. 2021

Clinical Cancer Research

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Purpose: Oncogenic fusions involving the neuregulin 1 (NRG1) gene are found in approximately 0.2% of cancers of diverse histologies. The resulting chimeric NRG1 proteins bind predominantly to HER3, leading to HER3-HER2 dimerization and activation of downstream growth and survival pathways. HER3 is, therefore, a rational target for therapy in NRG1 fusion-driven cancers.Experimental Design: We developed novel patient-derived and isogenic models of NRG1-rearranged cancers and examined the effect of the anti-HER3 antibody, seribantumab, on growth and activation of signaling networks in vitro and in vivo.Results: Seribantumab inhibited NRG1-stimulated growth of MCF-7 cells and growth of patient-derived breast (MDA-MB-175-VII, DOC4-NRG1 fusion) and lung (LUAD-0061AS3, SLC3A2-NRG1 fusion) cancer cells harboring NRG1 fusions or NRG1 amplification (HCC-95). In addition, seribantumab inhibited growth of isogenic HBEC cells expressing a CD74-NRG1 fusion (HBECp53-CD74-NRG1) and induced apoptosis in MDA-MB-175-VII and LUAD-0061AS3 cells. Induction of proapoptotic proteins and reduced expression of the cell-cycle regulator, cyclin D1, were observed in seribantumab-treated cells. Treatment of MDA-MB-175-VII, LUAD-0061AS3, and HBECp53-CD74-NRG1 cells with seribantumab reduced phosphorylation of EGFR, HER2, HER3, HER4, and known downstream signaling molecules, such as AKT and ERK1/2. Significantly, administration of seribantumab to mice bearing LUAD-0061AS3 patient-derived xenograft (PDX) and OV-10-0050 (ovarian cancer with CLU-NRG1 fusion) PDX tumors induced regression of tumors by 50%-100%. Afatinib was much less effective at blocking tumor growth.Conclusions: Seribantumab treatment blocked activation of the four ERBB family members and of downstream signaling, leading to inhibition of NRG1 fusion-dependent tumorigenesis in vitro and in vivo in breast, lung, and ovarian patient-derived cancer models.

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MAPK Pathway Alterations Correlate with Poor Survival and Drive Resistance to Therapy in Patients with Lung Cancers Driven by ROS1 Fusions

Cited by 41 publications

References 48 publications

Cases of ROS1-rearranged lung cancer: when to use crizotinib, entrectinib, lorlatinib, and beyond?

Cases of ROS1-rearranged lung cancer: when to use crizotinib, entrectinib, lorlatinib, and beyond?

Clinicopathologic, genomic and protein expression characterization of 356ROS1fusion driven solid tumors cases

The Anti-HER3 mAb Seribantumab Effectively Inhibits Growth of Patient-Derived and Isogenic Cell Line and Xenograft Models with Oncogenic NRG1 Fusions

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