My group uses genome-wide functional genetic approaches to identify powerful drug combinations, new drug targets and mechanisms of resistance to cancer drugs. We aim to bring our discoveries to the clinic in close collaboration with the clinicians of our affiliated hospital.
Pro-senescence therapies for the treatment of cancer
Induction of senescence represents a promising strategy for the treatment of cancer, especially when such pro-senescence therapy is followed by a second drug that selectively kills senescent cancer cells (senolytic agent). We published this year that such a “one-two punch” therapy is effective for the treatment of liver cancer. To make this approach more generally applicable, we have characterized a large panel of senescent cancer cells with the aim to find common vulnerabilities. We have performed CRISPR screens in senescent cancer cells to uncover such vulnerabilities. This resulted in the identification of several new candidate senolytic agents.
Combinatorial drugging the MAP kinase pathway
Resistance to targeted cancer drugs is thought to result from selective pressure exerted by a high drug dose. Partial inhibition of multiple components in the same oncogenic signaling pathway may add up to complete pathway inhibition, while decreasing the selective pressure on each component to acquire a resistance mutation. We have tested this Multiple Low Dose (MLD) therapy model in EGFR mutant NSCLC. We show that as little as 20% of the individual effective drug doses is sufficient to completely block MAPK signaling and proliferation when used in 3D (RAF+MEK+ERK) or 4D (EGFR+RAF+MEK+ERK) inhibitor combinations. Importantly, EGFR mutant NSCLC cells treated with MLD therapy do not develop resistance. Using several animal models, we found durable responses to MLD therapy without associated toxicity. Our data support the notion that MLD therapy could deliver clinical benefit, even for those having acquired resistance to third generation EGFR inhibitor therapy.
In 2018, we published that combined inhibition of PTPN11 and MEK leads to dramatic therapeutic effects in KRAS mutant lung cancer. We have also validated this concept in KRAS mutant pancreatic cancer with drugs that inhibit PTPN11 and the ERK kinases, in anticipation of the start of a clinical study with these drugs in pancreatic cancer in the course of 2020.
Collateral vulnerabilities of drug-resistant cells
Drug resistance is associated with a fitness cost that can be exploited therapeutically. In my research group we focus on the identification of vulnerabilities of cancer cells that are induced by drug resistance. As one example, we showed that resistance to BRAF inhibitors in melanoma is associated with an increased sensitivity to histone deacetylase inhibitors. This concept is currently undergoing clinical testing. Our current research focuses on acquired vulnerabilities of cells having gained resistance to targeted or chemotherapies.