Genomic Profiling Confirms MAPK/ERK Gene Alterations in Metastatic Prostate Cancer

Edwin Lin, MD/PhD Candidate

MAPK/ERK gene alterations, primarily receptor tyrosine kinases (RTKs), BRAF, and CDK4/6 amplifications, were found to be present in more than half of patients with heavily pretreated metastatic prostate cancer, according to findings from a large cohort that were presented during the 2019 ASCO Annual Meeting.

“RTKs, BRAF, and CDK4/6 amplifications are among the most frequent events, display recurrent patterns of co-alteration, and are targetable by existing drugs,” the study authors stated in their poster that was presented during the meeting. The study was led by Edwin Lin, MD/PhD Candidate at University of Utah School of Medicine, Huntsman Cancer Institute.

Prognosis continues to remain poor for patients with metastatic prostate cancer, who are known to eventually progress on the currently available therapies. However, in vitro models as well as small data sets have demonstrated that disease progression in prostate cancer is also associated with increased MAPK/ERK signaling, yet the molecular abnormalities that are known to cause the increased signaling have not been well defined.

Investigators sought to determine whether genomic profiling in the MAPK/ERK pathway in heavily pretreated patients with metastatic prostate cancer could uncover the genetic alterations, with the hope that some of these abnormalities could be targeted by existing targeted therapies.

In the study, researchers analyzed 2679 plasma samples from 2309 patients with metastatic prostate cancer via Guardant360, a circulating tumor DNA next-generation sequencing panel that sequences 73 clinically relevant cancer genes. The assay also profiles fusions, indels, and amplifications with high sensitivity and specificity. Via the REACTOME database, genes were assigned to gene sets that paralleled both biological pathways and molecular functional classes; this was followed by determining the summary statistics.

Results showed that 56% of samples harbored alterations in the MAPK/ERK signaling genes, and gene aberrations were most frequent in the MAPK pathway, RTK, and cell cycle control genes.

In the MAPK-ERK pathway genes, BRAF, RAF1, NF1, and KRAS, were the most frequently identified genes, followed by NRAS, HRAS, RIT1, PTPN11, and MAP2K1. Specifically, BRAF and RAF1 amplification were most prevalent.

In the RTK genes, MET, EGFR, FGFR1, PDGFRA, KIT, ERBB2, and FGFR2 were among the most commonly identified genes, specifically in amplification form. Other genes, at lower levels, included RET, ALK, FGFR3, DDR2, ROS1, and NTRK1. Also in the RTK genes, co-amplifications were found to be most frequent between MET and EGFR, as well as PDGFRA and KIT.

In the cell cycle control genes, CDK6 and MYC were the 2 genes were the largest number of events identified, followed by CCNE1, CCND1, RB1, CDK4, CCND2, CDKN2A, and FBXW7.

Moreover, researchers conducted a Bayesian network analysis, which demonstrated positive interdependencies between all of the MAPK/ERK gene sets.

“Future work to assess the biological and clinical significance of these recurrent patterns of alteration will pave the way for novel combinatorial treatments,” the authors concluded in the poster.

Lin E, Hahn AW, Sonpavde G, et al. Profiling of genomic alterations in MAPK/ERK signaling in a large cohort of metastatic prostate cancer (mPC) patients. J Clin Oncol. 2019;37(suppl; abstr 5032). doi: 10.1200/JCO.2019.37.15_suppl.5032.