The present invention relates to the treatment of cancer using combination therapy comprising a dual modulator of Insulin Receptor Substrate (IRS) and signal transducer and activator of transcription 3 (Stat3), in combination with (i) a modulator of a protein kinase (PK) selected from an Epidermal Growth Factor inhibitor (EGFR inhibitor) and EGFR antibody； (ii) an inhibitor of mammalian target of rapamycin (m TOR)； (iii) a mitogen- activated protein kinase (MEK) inhibitor； (iv) a mutated B-Raf inhibitor； (v) a chemotherapeutic agent like Gemcitabine, 5-FU, Irinotecan and Oxaliplatin； and (vi) certain combinations thereof. The combination can be used to treat a tumor that has developed resistance to an EGFR inhibitor, EGFR antibody, m TOR inhibitor, MEK inhibitor, mutated B-Raf inhibitor, chemotherapeutic agents, and certain combinations thereof, or to prevent acquired resistance of a tumor to any of said inhibitors or agents, or to prevent tumor recurrence following cease of treatment with any of said inhibitors or agents or a combination thereof. The combination provides a therapeutic effect which is at least additive, and is preferably synergistic. The present invention further relates to the treatment of cancer using combination therapy comprising a dual modulator of IRS and Stat3, in combination with an immunotherapy agent. The combination can be used to sensitize a tumor to immunotherapy.
