Insulin receptor substrates 1 and 2 (IRS1/2) mediate mitogenic and anti-apoptotic signaling from insulin-like growth factor 1 receptor (IGF1R), insulin receptor (IR) and other oncoproteins. IRS1 plays a central role in cancer cell proliferation, its expression is increased in many human malignancies and its up-regulation mediates resistance to anti-cancer drugs. IRS2 is associated with cancer cell motility and metastasis. Currently there are no anti-cancer agents that target IRS1/2. We present new IGF1R/IRS-targeted agents (NT compounds) that promote inhibitory Ser-phosphorylation and degradation of IRS1 and IRS2. Elimination of IRS1/2 results in long-term inhibition of IRS1/2-mediated signaling. The therapeutic significance of this inhibition in cancer cells was demonstrated while unraveling a novel mechanism of resistance to B-RAFV600E/K inhibitors. We found that IRS1 is up-regulated in PLX4032-resistant melanoma cells and in cell lines derived from patients whose tumors developed PLX4032 resistance. In both settings, NT compounds led to elimination of IRS proteins and evoked cell death. Treatment with NT compounds in vivo significantly inhibited the growth of PLX4032-resistant tumors, and displayed potent anti-tumor effects in ovarian and prostate cancers. Our findings offer preclinical proof of concept for IRS1/2 inhibitors as cancer therapeutics including in PLX4032-resistant melanoma. By the elimination of IRS proteins, such agents should prevent acquisition of resistance to mutated-B-RAF inhibitors and possibly restore drug sensitivity in resistant tumors.