Neomorphic PDGFRA extracellular domain driver mutations are resistant to PDGFRA targeted therapies

Nat Commun. 2018 Nov 2;9(1):4583. doi: 10.1038/s41467-018-06949-w.

Carman K M Ip ¹, Patrick K S Ng ², Kang Jin Jeong ³, S H Shao ², Zhenlin Ju ⁴, P G Leonard ⁵ ⁶, Xu Hua ³, Christopher P Vellano ⁷, Richard Woessner ⁸, Nidhi Sahni ³ ⁹, Kenneth L Scott ¹⁰, Gordon B Mills ³ ²

Affiliations

1 Department of Systems Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA. [email protected].
2 Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
3 Department of Systems Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
4 Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
5 Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, 1881 East Road, Houston, TX, 77054, USA.
6 Core for Biomolecular Structure and Function, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, 1881 East Road, Houston, TX, 77054, USA.
7 Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
8 Cancer Bioscience, in vivo Cancer Pharmacology, AstraZeneca Phamaceuticals, Boston, MA, 02451, USA.
9 Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, 1808 Park Rd 1C, Smithville, TX, 78957, USA.
10 Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Suite 450A, Houston, TX, 77030, USA.

PMID: 30389923 DOI: 10.1038/s41467-018-06949-w

Abstract

Activation of platelet-derived growth factor receptor alpha (PDGFRA) by genomic aberrations contributes to tumor progression in several tumor types. In this study, we characterize 16 novel PDGFRA mutations identified from different tumor types and identify three previously uncharacterized activating mutations that promote cell survival and proliferation. PDGFRA Y288C, an extracellular domain mutation, is primarily high mannose glycosylated consistent with trapping in the endoplasmic reticulum (ER). Strikingly, PDGFRA Y288C is constitutively dimerized and phosphorylated in the absence of ligand suggesting that trapping in the ER or aberrant glycosylation is sufficient for receptor activation. Importantly, PDGFRA Y288C induces constitutive phosphorylation of Akt, ERK1/2, and STAT3. PDGFRA Y288C is resistant to PDGFR inhibitors but sensitive to PI3K/mTOR and MEK inhibitors consistent with pathway activation results. Our findings further highlight the importance of characterizing functional consequences of individual mutations for precision medicine.

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