Abstract Pancreatic cancer is an extremely lethal disease, which is mostly associated with the gain-of-function mutation in KRAS gene. Due to a very high frequency of activating mutations within the KRAS gene, mutant KRAS is considered a rational therapeutic target in pancreatic cancer. In line with the existing idea that oncogenic KRAS is required for the maintenance of pancreatic cancer, we show a complete macroscopic regression of both primary and orthotopically transplanted tumors in our ligand-regulatable (Doxycycline) mouse model of KRASG12D-driven pancreatic cancer. This finding indicate that the expression, and provides a strong rationale for the development of KRAS targeted therapy for the treatment of pancreatic cancer. However, in our current study, despite the complete macroscopic regression of PDACs upon downregulation of oncogenic KRAS, few cancer cells always survived and remained dormant for a protracted duration. These residual cancer cells were responsible for the rapid recurrence upon KRAS reactivation. Using a genome-wide gene expression (RNA-Seq) analysis of in vivo-derived bulk and residual cancer cells followed by biochemical analysis, we identified a significant increase in autocrine IGF-1/AKT signaling in residual cancer cells. We also identified IGF1 signaling as a common survival mechanism of residual cancer cells in c-MYC-driven pancreatic tumor model. Pharmacological inhibition of IGF-1R signaling significantly delayed the tumor recurrence in both the tumor models, suggesting the crucial role of IGF-1R signaling in the survival of cancer cells in the absence of oncogenic drivers. Our findings from animal models were also validated in human pancreatic cancer cell lines harboring KRAS mutations, by demonstrating a compensatory increase in IGF1 signaling in response to a conditional knockdown of KRAS in vitro and in vivo. Collectively, all our findings from mouse model and human cancer cell studies strongly indicate that residual cancer cells can survive in the absence of tumor driving oncogenes by upregulation of autocrine IGF1 signaling loop. Thus, targeting oncogenic drivers along with IGF-1R signaling might be an effective strategy for prevention of tumor recurrence in pancreatic cancer. Citation Format: Nirakar Rajbhandari. Autocrine IGF1 signaling mediates the survival of pancreatic cancer cells following the ablation of oncogenes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1848. doi:10.1158/1538-7445.AM2017-1848