Acquired resistance to EGFR tyrosine kinase inhibitors such as osimertinib involves both EGFR resistance mutations and EGFR-independent mechanisms (e.g., activation of alternate receptor tyrosine kinases). Sun and colleagues reported the discovery of IACS-13909, an allosteric inhibitor of SHP2 that is able to overcome both types of resistance mechanisms in preclinical models. Targeting SHP2 may present a promising strategy to tackle the plasticity and heterogeneity of tyrosine kinase inhibitor resistance. For details, see article by Sun and colleagues on page 4840.