Personalizing cancer treatment in the age of global genomic analyses: PALB2 gene mutations and the response to DNA damaging agents in pancreatic cancer.
Metastasis and drug resistance are the major causes of mortality in patients with pancreatic cancer. Once developed, the progression of pancreatic cancer metastasis is virtually unstoppable with current therapies. Here, we report the remarkable clinical outcome of a patient with advanced, gemcitabine-resistant, pancreatic cancer who was later treated with DNA damaging agents, on the basis of the observation of significant activity of this class of drugs against a personalized xenograft generated from the patient's surgically resected tumor. Mitomycin C treatment, selected on the basis of its robust preclinical activity in a personalized xenograft generated from the patient's tumor, resulted in long-lasting (36+ months) tumor response. Global genomic sequencing revealed biallelic inactivation of the gene encoding PalB2 protein in this patient's cancer; the mutation is predicted to disrupt BRCA1 and BRCA2 interactions critical to DNA double-strand break repair. This work suggests that inactivation of the PALB2 gene is a determinant of response to DNA damage in pancreatic cancer and a new target for personalizing cancer treatment. Integrating personalized xenografts with unbiased exomic sequencing led to customized therapy, tailored to the genetic environment of the patient's tumor, and identification of a new biomarker of drug response in a lethal cancer.
Corresponding Author: Manuel Hidalgo, Clinical Research Program, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro, 3, 28029, Madrid, Spain.
Maria C
MC
Villarroel
N V
NV
Rajeshkumar
Ignacio
I
Garrido-Laguna
Ana
A
De Jesus-Acosta
Siân
S
Jones
Anirban
A
Maitra
Ralph H
RH
Hruban
James R
JR
Eshleman
Alison
A
Klein
Daniel
D
Laheru
Ross
R
Donehower
Manuel
M
Hidalgo
D000818:Animals; D053903:DNA Breaks, Double-Stranded; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D000076164:Fanconi Anemia Complementation Group N Protein; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D016685:Mitomycin / Q000627:therapeutic use*; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D057285:Precision Medicine / Q000379:methods; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; C512790:PALB2 protein, human; D025521:Tumor Suppressor Proteins; D003841:Deoxycytidine; D016685:Mitomycin; D000093542:Gemcitabine