Provided herein are methods of treating a patient having a cancer that exhibits (i) a hemizygous loss of the TP53 gene (ii) a hemizygous loss of the POLR2A gene and/or (iii) a decreased level of expression of a POLR2A gene product relative to a reference (i.e. control) expression level. The methods comprise administering a therapeutically effective amount of a POLR2A inhibitor (e.g. a nucleic acid that inhibits the expression of a POLR2A protein an amatoxin alpha amanitin or alpha amanitin conjugated to a cell targeting moiety such as an EpCAM antibody) to a patient having or determined to have (i) a hemizygous loss of the TP53 gene (ii) a hemizygous loss of the POLR2A gene and/or (iii) a decreased level of expression of a POLR2A gene product relative to a reference (i.e. control) level.
