Methods of diagnosing and treating cancer in patients having or developing resistance to a first cancer therapy

A method of treating cancer in a first subject in need thereof, the method comprising:

• identifying a first subject having an increased gene copy number or an alteration in mRNA expression or protein overexpression or phosphorylation of one or more kinase targets in cancer cells of the first subject relative to cells of a second subject without the cancer, the one or more kinase targets selected from the group consisting of MAP3K8 (TPL2/COT), CRKL(CrkL), FGR (Fgr), PRKCE (Prkce), PRKCH (Prkch), ERBB2 (ErbB2), AXL (Axl), and PAK3 (Pak3);
• and
• administering to the first subject an effective amount of a RAF inhibitor selected from the group consisting of RAF265, sorafenib, SB590885, PLX 4720, PLX4032, GDC-0879 and ZM 336372, and an effective amount of a second inhibitor, wherein the second inhibitor is a MAP3K8 (TPL2/COT) inhibitor selected from the group consisting of 4-(3-chloro-4-fluorophenylamino)-6-(pyridin-3-ylmethylamino)-3-cyano-[1,7]-naphthyridine, the inhibitory RNA of SEQ ID NO:
• 16, and the inhibitory RNA of SEQ ID NO:
• 17.