Missing content? – Request curation!
Request curation for specific Genes, Variants, or PubMed publications.
Have questions, comments, or suggestions? - Let us know!
Email us at : ckbsupport@jax.org
Ref Type | Journal Article | ||||||||||||
PMID | (32122926) | ||||||||||||
Authors | Sato H, Schoenfeld AJ, Siau E, Lu YC, Tai H, Suzawa K, Kubota D, Lui AJW, Qeriqi B, Mattar M, Offin M, Sakaguchi M, Toyooka S, Drilon A, Rosen NX, Kris MG, Solit D, De Stanchina E, Davare MA, Riely GJ, Ladanyi M, Somwar R | ||||||||||||
Title | MAPK Pathway Alterations Correlate with Poor Survival and Drive Resistance to Therapy in Patients with Lung Cancers Driven by ROS1 Fusions. | ||||||||||||
|
|||||||||||||
URL | |||||||||||||
Abstract Text | ROS1 tyrosine kinase inhibitors (TKI) provide significant benefit in lung adenocarcinoma patients with ROS1 fusions. However, as observed with all targeted therapies, resistance arises. Detecting mechanisms of acquired resistance (AR) is crucial to finding novel therapies and improve patient outcomes.ROS1 fusions were expressed in HBEC and NIH-3T3 cells either by cDNA overexpression (CD74/ROS1, SLC34A2/ROS1) or CRISPR-Cas9-mediated genomic engineering (EZR/ROS1). We reviewed targeted large-panel sequencing data (using the MSK-IMPACT assay) patients treated with ROS1 TKIs, and genetic alterations hypothesized to confer AR were modeled in these cell lines.Eight of the 75 patients with a ROS1 fusion had a concurrent MAPK pathway alteration and this correlated with shorter overall survival. In addition, the induction of ROS1 fusions stimulated activation of MEK/ERK signaling with minimal effects on AKT signaling, suggesting the importance of the MAPK pathway in driving ROS1 fusion-positive cancers. Of 8 patients, 2 patients harbored novel in-frame deletions in MEK1 (MEK1delE41_L54) and MEKK1 (MEKK1delH907_C916) that were acquired after ROS1 TKIs, and 2 patients harbored NF1 loss-of-function mutations. Expression of MEK1del or MEKK1del, and knockdown of NF1 in ROS1 fusion-positive cells activated MEK/ERK signaling and conferred resistance to ROS1 TKIs. Combined targeting of ROS1 and MEK inhibited growth of cells expressing both ROS1 fusion and MEK1del.We demonstrate that downstream activation of the MAPK pathway can mediate of innate acquired resistance to ROS1 TKIs and that patients harboring ROS1 fusion and concurrent downstream MAPK pathway alterations have worse survival. Our findings suggest a treatment strategy to target both aberrations. |
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 |
---|---|---|---|---|---|
MAP2K1 | E41_L54del | deletion | gain of function | MAP2K1 E41_L54del results in the deletion of 14 amino acids in the Map2k1 protein from amino acids 41 to 54 (UniProt.org). E41_L54del results in increased Map2k1 nuclear localization, elevated Erk phosphorylation, and cell transformation in culture, and promotes tumorigenesis and confers resistance to ROS1 tyrosine kinase inhibitors in the context of a ROS1 fusion (PMID: 32122926). | Y |
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
---|---|---|---|---|---|---|---|
MAP2K1 E41_L54del | lung cancer | sensitive | Cobimetinib | Preclinical - Cell culture | Actionable | In a preclinical study, Cotellic (cobimetinib) inhibited growth of transformed human lung cells expressing MAP2K1 E41_L54del in culture (PMID: 32122926). | 32122926 |
MAP2K1 E41_L54del | Advanced Solid Tumor | sensitive | Selumetinib | Preclinical - Cell culture | Actionable | In a preclinical study, Koselugo (selumetinib) inhibited growth of transformed cells expressing MAP2K1 E41_L54del in culture (PMID: 32122926). | 32122926 |
MAP2K1 E41_L54del | lung cancer | no benefit | LY3009120 | Preclinical - Cell culture | Actionable | In a preclinical study, transformed human lung cells expressing MAP2K1 E41_L54del were not sensitive to LY3009120 in culture (PMID: 32122926). | 32122926 |
MAP2K1 E41_L54del | Advanced Solid Tumor | no benefit | LY3009120 | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells expressing MAP2K1 E41_L54del were not sensitive to LY3009120 in culture (PMID: 32122926). | 32122926 |
MAP2K1 E41_L54del | Advanced Solid Tumor | sensitive | Trametinib | Preclinical - Cell culture | Actionable | In a preclinical study, Mekinist (trametinib) inhibited growth of transformed cells expressing MAP2K1 E41_L54del in culture (PMID: 32122926). | 32122926 |
MAP2K1 E41_L54del | lung cancer | sensitive | Trametinib | Preclinical - Cell culture | Actionable | In a preclinical study, Mekinist (trametinib) inhibited growth of transformed human lung cells expressing MAP2K1 E41_L54del in culture (PMID: 32122926). | 32122926 |
MAP2K1 E41_L54del | Advanced Solid Tumor | sensitive | Cobimetinib | Preclinical - Cell culture | Actionable | In a preclinical study, Cotellic (cobimetinib) inhibited growth of transformed cells expressing MAP2K1 E41_L54del in culture (PMID: 32122926). | 32122926 |
MAP2K1 E41_L54del | lung cancer | sensitive | Selumetinib | Preclinical - Cell culture | Actionable | In a preclinical study, Koselugo (selumetinib) inhibited growth of transformed human lung cells expressing MAP2K1 E41_L54del in culture (PMID: 32122926). | 32122926 |