In their lifetime, 1 in 2 men and 1 in 3 women are diagnosed with invasive cancer. The perpetuation of a tumor hinges largely on cancer cell-intrinsic signals maintaining tumor growth and the tumor’s ability to evade destruction by the immune system (Obenauf and Massagué, 2015). These dependencies are exploited by targeted therapies, which inhibit cancer cell-intrinsic signaling pathways, and immunotherapies, which unleash an immune response against cancer cells. Targeted therapies and immunotherapies have shown remarkable success in subgroups of patients, but therapy resistance and low response rates pose daunting challenges (Haas et al., 2018). The combination of different therapies is a promising path to overcome low response rates and acquired resistance. However, rational combination and optimal sequencing of therapies are hampered by a lack of molecular insight into resistance mechanisms and the interplay of therapies.
Our lab studies the molecular determinants of response and resistance to targeted and immunotherapies with the vision and mission to guide rational combination therapies to achieve durable responses in cancer patients. We aim to answer fundamental questions in cancer biology, such as: How is immune evasion facilitated? What contribution have the oncogenic pathways that drive tumor initiation in evading the immune system during metastasis or therapies? How are cancer cells and their microenvironment evolving during the inhibition of oncogenic pathways or the stimulation of an immune response? Which challenges and opportunities arise from this?
We study these general principles in MAPK-driven cancers of different cellular contexts, including melanoma, lung, colorectal, and pancreatic cancer, which represent cancer types with high to low capacity to respond to immunotherapies and are amenable to the treatment with MAPK inhibitors (BRAFi, MEKi, and the newly developed KRASi) (Obenauf et al., 2015). In addition, a sub-group of the lab investigates the molecular drivers rare skin cancers, such as Merkel cell carcinoma (Leiendecker, Jung, et al., 2020). For our studies we use human and murine cell line models, which easily allow the functional perturbation of candidate genes and can be transplanted in vivo to study interactions with the tumor stroma and a functional immune cell compartment. To complement these studies, we use patient derived xenograft models, genetically engineered mouse models, and co-culture systems and work closely with clinicians to cross-validate our findings in patient data. We are developing novel tools (e.g. CaTCH, Umkehrer et al., 2020), perform whole genome CRISPR screens with various readouts, and a whole plethora of biochemical and genetic approaches to uncover novel mechanistic insights.