PXD036772

PXD036772 is an original dataset announced via ProteomeXchange.

Title	Mig6 mediates adaptive and acquired resistance to ALK and ROS1 fusion kinase inhibition through feedback activation of EGFR: H3122
Description	ALK and ROS1 fusions defines subsets of lung adenocarcinoma. Although ALK/ROS1 inhibitors improved therapeutic outcome of patients harboring those oncogenic fusions, complete responses were rare, and resistance eventually develops from the residual tumor. To under the mechanisms contributing to residual tumor formation, we performed phosphoproteomics to explore the signaling adaption shortly after ALK/ROS1 inhibition. We found the phosphorylation of Mig6, a potent inhibitor for EGFR, was decreased following ALK/ROS1 inhibition, impairing Mig6 binding and inhibition on EGFR. Furthermore, Mig6 mRNA and protein levels were decreased rapidly by ALK/ROS1 inhibitors, potentiating EGFR activity to support cell survival. We also uncovered a novel mechanism mediated by Mig6 to regulate EGFR activity without impacting EGFR phosphorylation, but rather altering signaling adaptor SHC1 binding to EGFR. Mig6 expression was also lost following long-term exposure to ALK/ROS1 inhibitors to support EGFR-mediated acquired resistance. Finally, a Mig6 EGFR-binding domain truncation mutation was identified in a patient-derived ROS1 cell line, rendering its resistance to ROS1 inhibitors but sensitivity to HER family inhibitors. Our work established a rationale to evaluate combinations of ALK/ROS1 and EGFR inhibitors to limit residual tumor formation, therefore preventing or delaying subsequent resistance emergence.
HostingRepository	PRIDE
AnnounceDate	2023-09-12
AnnouncementXML	Submission_2023-09-12_09:07:02.484.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD036772
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	JohnKoomen
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2022-09-17 02:26:01	ID requested
⏵ 1	2023-09-12 09:07:02	announced

10.6019/PXD036772;

submitter keyword: Lung Cancer, Kinase Inhibitor, Anaplastic Lymphoma Kinase, Drug Resistance

RobertDoebele
contact affiliation	University of Colorado-Anschutz Campus
contact email	ROBERT.DOEBELE@CUANSCHUTZ.EDU
lab head
JohnKoomen
contact affiliation	Moffitt Cancer Center
contact email	john.koomen@moffitt.org
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD036772
     1. Label: PRIDE project
     2. Name: Mig6 mediates adaptive and acquired resistance to ALK and ROS1 fusion kinase inhibition through feedback activation of EGFR: H3122