Roger Lo, MD, PhD

Today oncologists have in their arsenal highly active and precise systemic therapies but often times cannot predict which patients would benefit the most. A major contributor to this knowledge gap is the cancer’s ability to resist therapies. Here, we will focus on malignant melanoma, an aggressive type of skin cancer, where two major precision-oncology therapies were first developed. One targets the so-called ‘MAPK cancer pathway’ that sustains the growth of many cancer types, not just melanoma. The other consists of immune checkpoint blockade (ICB) therapy, which unleashes the body’s cancer-killing immune cells and has been approved in >30 cancer types. In patients with melanoma, >70% and >40% of patients respond initially to MAPK targeted and ICB therapies, respectively. However, after initial responses, ~20-40% of patients experience relapse due to their melanomas developing resistance to therapies. In this study, we dissect how melanomas evolve resistance so that we can prevent resistance. In response to therapies, melanoma and other cancers diversify their genetic makeup, creating new species, and this diversity increases their chance of survival or ‘fitness’ through Darwinian natural selection. We will identify ways in which melanomas diversify in response to these two pillars of modern-day cancer treatment in order to construct new therapies to prevent cancers from coming back. Preventing resistance will spare patients from the emotional and physical tolls of clinical relapses and surgical and radiation therapies to control resistant tumors. Ultimately, preventing resistance will improve the patients’ quality and quantity of life and reduce financial tolls.