All cancer therapies, dating back to the early use of radiation and chemotherapy, have been plagued by the challenge of acquired resistance, where the initial treatment intervention appears successful but is followed by relapse (often fulminant), coupled with failure to respond to repeat administration of the initial therapy. Mechanistic insight into the cause of relapse was initially lacking, largely due to a poor understanding of the mechanisms of action of most chemotherapies, but this changed with the advent of targeted cancer therapy, where a precise molecular understanding of the drug target provided a foothold into deciphering potential mechanisms of acquired resistance. A clear demonstration of the power of this approach came with the discovery of the BCR-ABL T315I gatekeeper mutation that confers resistance to the ABL kinase inhibitor imatinib (Gleevec) in patients with chronic myeloid leukemia. Shortly thereafter, the analogous EGFR T790M gatekeeper mutation was shown to confer resistance to first generation EGFR inhibitors in lung cancer. These and other examples have proven instructive in designing next generation inhibitors that limit or restrict the potential for “on target” escape mechanisms, with asciminib (for CML) and osimertinib (for EGFR mutant lung cancer) serving as instructive examples.
While next generation targeted therapies clearly extend response duration (and in some cases survival), this comes at a cost. An unintended consequence of increased selective pressure on the primary cancer driver oncogene has been the emergence of “off target” resistance, where cancers relapse despite sustained and potent target inhibition by the initial therapy. Two flavors of “off target” escape have emerged. The first is often called “bypass” to reflect the restoration of oncogenic signaling downstream from the point of initial target blockade. “Bypass” resistance can, in principle, be addressed through appropriate combination therapy, as is the case with BRAFi + MEKI (for melanoma) and EGFRi + METi (for lung cancer). However, the second flavor of “off target” resistance is more daunting. In this case, tumors escape dependency on the driver oncogene by undergoing a “cell state” or lineage transition that renders them free from the consequences of targeted inhibition. A dramatic example is fulminant neuroendocrine cancer that can emerge in patients with lung and prostate adenocarcinoma treated with the respective adenocarcinoma-focused targeted therapies. Much attention is now focused on unraveling the series of genetic and epigenetic events that enable tumor cells to undergo such a dramatic identity change, with current evidence pointing to a reawakening of long silenced developmental pathways (largely driven by transcription factors). I will discuss our efforts to unravel the molecular details of the adeno-to-neuroendocrine transition in prostate cancer, focusing on opportunities for therapeutic intervention.