Targeted cancer therapies that focus on specific mutations have shown promise, but tumors frequently develop resistance. Researchers at the University of California, San Diego School of Medicine and Moores Cancer Center have identified a promising three-pronged drug strategy that overcomes resistance mechanisms in glioblastoma, the most common and aggressive primary brain tumor.
Published May 5 in Oncotarget, the study demonstrates that combining three different classes of anti-cancer agents — an Epidermal Growth Factor Receptor (EGFR) inhibitor, a PLK1 inhibitor that elevates cellular stress, and a DNA-damaging chemotherapy — produces durable tumor control in both a mouse model of glioblastoma and in patient-derived glioblastoma tissue cultured in the laboratory.
In approximately half of glioblastomas, mutations in EGFR drive uncontrolled cell growth by decoupling tumor cells from normal environmental growth signals. Although highly specific EGFR-targeting drugs exist, glioblastomas often evade these treatments by activating alternative receptors or signaling pathways. “Treating glioblastoma is like a chess match,” said senior author Clark C. Chen, MD, PhD, associate professor of neurosurgery and vice-chair for Research and Academic Development at UC San Diego. “Each therapeutic move prompts a counter-move by the tumor, so effective therapy requires coordinated, multi-targeted strategies.”
The investigators focused on PLK1, a protein that helps glioblastoma cells manage the stress caused by their oncogenic alterations and accumulated DNA damage. The team found that glioblastoma cells that become resistant to EGFR inhibitors remain dependent on PLK1 for survival. This persistent dependency suggested that combining PLK1 inhibition with EGFR inhibition could expose vulnerabilities in tumor cells that single-agent therapies leave intact.
In controlled experiments, treating mice or patient-derived tumor explants with a single agent — either an EGFR inhibitor, a PLK1 inhibitor, or temozolomide (TMZ), the standard DNA-damaging chemotherapy for glioblastoma — produced only temporary tumor control. Tumors eventually recurred despite these individual responses. However, when all three drug classes were given together, researchers observed no detectable tumor recurrence in the treated mice over the study period. The combination was tolerated without obvious, significant side effects in the animal models used.
“It’s often assumed that simply blocking a cancer-causing mutation will cure the disease,” said co-author Bob S. Carter, MD, PhD, chief of neurosurgery at UC San Diego. “Our findings show a more nuanced reality: tumors exploit compensatory mechanisms, and exploiting those dependencies — such as PLK1 reliance — can guide more effective combination therapies.”
The specific agents used in the experimental regimen were BI2536 (a PLK1 inhibitor), gefitinib (an EGFR inhibitor), and temozolomide (TMZ), the current clinical standard for glioblastoma chemotherapy. While the safety and tolerability of this exact three-drug combination in human patients remains to be established, each drug has an established clinical profile. Gefitinib and TMZ are well-characterized in cancer care, and PLK1 inhibitors including BI2536 have shown acceptable tolerability in early clinical trials, with at least one PLK1 inhibitor having advanced into Phase III trials for another cancer type.
The study team included researchers from UC San Diego, Shanghai Jiao Tong University, Dana-Farber Cancer Institute, Duke University Medical Center, Queen’s University Belfast, the University of Oxford, the Mayo Clinic and Ludwig Cancer Research. Co-authors are Ying Shen, Jie Li, Diahnn Futalan, Tyler Steed, Jeffrey M. Treiber, Zack Taich, Masayuki Nitta, Deanna Stevens, Jill Wykosky, Frank B. Furnari, Webster K. Cavenee, Arshad Desai, Hong-Zhuan Chen, Oren J. Becher, Richard Kennedy, Fumiko Esashi, and Jann N. Sarkaria, among others.
Funding: This research received support in part from the Sontag Foundation, the Burroughs Wellcome Fund, the Kimmel Foundation, the Doris Duke Foundation, and the Forbeck Foundation.
Source: Heather Buschman, UC San Diego Health System. Image credit: UC San Diego Health System. Original research published May 5, 2015 in Oncotarget under the title “Orthogonal targeting of EGFRvIII expressing glioblastomas through simultaneous EGFR and PLK1 inhibition.”
Abstract
Orthogonal targeting of EGFRvIII-expressing glioblastomas through simultaneous EGFR and PLK1 inhibition
The authors report a synthetic-lethal interaction between PLK1 suppression and expression of the oncogenic EGFRvIII variant. PLK1 supports homologous recombination and helps tumor cells offset DNA damage and oncogenic stress caused by EGFRvIII. Inhibiting PLK1 increased sensitivity to temozolomide (TMZ), amplifying DNA damage and cytotoxicity. This sensitizing effect was more pronounced in EGFRvIII-driven glioblastoma models than in models driven by other oncogenes. Importantly, BI2536 enhanced the anti-tumor effects of EGFR inhibitors across multiple tumor clones that had independently developed resistance to EGFR blockade, indicating those resistant cells still depended on PLK1-mediated stress mitigation. Although combining an EGFR inhibitor with BI2536 improved responses in the model systems, durable tumor control required adding TMZ. These results support a “multi-orthogonal” combination approach that targets both the cancer-driving mutation and the compensatory pathways tumors use to survive.