Approved KRAS inhibitors have shown limited therapeutic benefit over standard chemotherapy in PDAC and often encounter acquired resistance due to additional genetic alterations. RAS and RB1 functionally antagonize each other, which explains why RB1 is rarely mutated in KRAS-driven tumors. In PDAC cells, CDK4/6 inhibition induced cellular senescence accompanied by partial apoptosis. However, additional treatment with a senolytic agent or an ERK inhibitor promoted more efficient tumor cell elimination. While CDK4/6 inhibition downregulated KRAS activity, it concurrently upregulated EGFR signaling in a SASP and JNK-dependent manner. Deprivation of EGFR signaling after CDK4/6 inhibition triggered apoptosis in senescent cells in a manner similar to the treatment with a senolytic agent. In contrast, specific inhibition of KRAS induced modest enhancement of EGFR activity and SASP in a JNK-independent manner. Collectively, our study proposes that the CDK4/6 inhibitor may achieve greater therapeutic efficacy when combined with the EGFR inhibitor than KRAS inhibitor monotherapy.