NSCLC is diagnosed in an estimated 220,000 patients each year with five-year overall survival rates of 16 percent. A recent report confirmed that 16 percent of NSCLC patients carry oncogenic KRAS mutation. Patients with KRAS mutation often harbored in wild-type EGFR tumors, are resistant to Tyrosine Kinase Inhibitors (TKI). A potent drug targeted against KRAS mutation has not yet been developed and the objective response rate with the current standard of care is a meager three percent. Interestingly, KRAS knockdown using siRNA sensitizes tumor to TKI with a good response rate. Retroviral vectors, liposomes, polymeric particles and metallic nanoparticles have been used as carriers to deliver siRNA within cancer-site. However, protecting siRNA from serum degradation and cytoplasmic delivery are two major issues. Also, in most cases, a mere siRNA mediated oncogene knockdown does not have significant impact on the cancer cell apoptosis since the cells adapt to another effector survival pathway. To overcome these challenges and understand the adopted effector downstream mechanism post oncogene knockdown, we hierarchically created a well-defined 200nm tri-block nanocomplex with each sublayer contributing to a definite function. The nanocomplex comprises of an enzymatically cleavable protein (gelatin) nanoparticle encapsulated with a TKI (gefitinib) and surface functionalized with an antibody (Cetuximab)-siRNA (Kras G12C) conjugate. Detailed characterization revealed each nanoparticle of the tri-block nanocomplex comprised of ∼400 antibodies and ∼800 siRNA. We protected 14KDa siRNA within 150KDa cetuximab and sandwiched it between antibody and gelatin nanoparticle to protect from serum degradation, confirmed using SDS-PAGE. To investigate cellular activity, we incubated the nanocomplex in drug resistant Kras G12C mutant NSCLC (H23 cells). The nanocomplex, when delivered to cytoplasm of the drug resistant H23 cells for oncogene knockdown, sensitized the affected cells to the co-delivered TKI. Knockdown of the oncogene was confirmed by monitoring the PI3K and MAPK downstream protein expression levels. Western blot results indicated abrogation of activated PI3K and MAPK pathway proteins. In vitro assays revealed 95% toxicity for the nanocomplex containing 5μM gefitinib as against 0-10% toxicity for 5μM stand-alone gefitinib. rtPCR showed downregulation of DUSP6, a known effect for H23 cells with knocked down oncogene. Flow cytometry results showed 2 fold higher internalization of the nanocomplex compared to transfected siRNA. However, in the absence of TKI, the nanocomplex showed no toxicity suggesting the cells adapt to a parallel effector pathway for survival, although phosphorylated Mek, Erk and Akt were downregulated leading us to investigate a possible survival mechanism. We hypothesized that the downstream signaling is governed by Gab1 assisted pathway. In H23 cells, activated ERK results in phosphorylation of Gab1 on serine and threonine residues and forms Gab1-p85 PI3K complex that are adjacent to p85 PI3K binding sites. Knocking down the oncogene dephosphorylated Erk, and negated the complex formation. This further cascaded in tyrosine phosphorylation at Tyr627 domain of Gab1, which is known to associate with downstream of EGFR but upstream of Ras, to regulate EGFR signaling through several positive feedback loops. We found that TKI binds to this specific phosphotyrosine domain of Gab1, the domain that is responsible for Gab1-Egfr association. In the absence of a TKI, the feedback loop mediated via Gab1 provides a route for survival but is sensitized by abrogation of Gab1-Egfr complex formation post oncogene knockdown when exposed to a TKI. The outcome of this study provides a potential solution for treating patients harboring KRAS mutation.