Jillian Wise, PhD

Rank

Instructor

Department

MGH

Center for Cancer Research

Authors

Jillian F. Wise*, Marcello Stanzione, Alice Zheng, Jun Zhong, Edmond Wong, Adam Acker, Adam Langenbucher, Ramin Sakhtemani, Robert Manguso, Nicholas J. Dyson, Ben J. Drapkin and Michael S. Lawrence

Principal Investigator

Michael S. Lawrence

Twitter / Website

Categories

Genome-wide analysis of therapeutically induced mutations in small cell lung cancer reveals potential vulnerability to immune checkpoint blockade with temozolomide and Olaparib treatment

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Abstract

A major contributor to cancer mortality is the ability of cancer cells to evolve and evade killing by therapies. This tumor evolution manifests clearly in small-cell lung cancer (SCLC). Despite initial response to therapy, nearly all patients relapse and develop resistance to multiple treatments. Genomic advancements have resulted in partial decoding of the patterns left behind on DNA from chemical carcinogens and therapeutic agents acting on cancer cells. Despite current knowledge on genomic alterations incurred during therapy, there is a clear underutilization of this information in therapy development. We sought to study the genetic alterations induced by SCLC therapies in order to target potential genomic vulnerabilities. We performed whole-genome sequencing on a unique cohort of patient-derived xenograft (PDX) models of SCLC enriched in relapsed models. We revealed a unique pattern of DNA damage in patients treated with the chemotherapy agent temozolomide (TMZ) and a poly-ADP-ribose polymerase (PARP) inhibitor. Part of this distinctive pattern was a striking increase in the mutation burden of highly expressed genes. This is opposite from the usual trend of mutations being enriched in low-expression regions. Given the relationship between gene expression and protein levels, we postulated that an increase in mutations of highly expressed genes will result in an increase in mutated peptides displayed on cells by the antigen presentation pathway. We computationally determined that TMZ-induced mutations increased the pool of neoantigens for presentation to the immune system. We then determined that TMZ and Olaparib (OT) treatment followed by immune checkpoint blockade (ICB) therapy sensitized an SCLC cell line to immune cell co-culture related death. Critically, ongoing damage measured through a lactose dehydrogenase reporter occurred in OT-treated cells at higher rates than in untreated cells without addition of anti-PDL1. Our work indicates that ICB treatment after OT relapse may be effective in the clinic.