Figure 6. Proposed model for IACS-13909 in overcoming both EGFR-dependent and EGFR-independent osimertinib resistance mechanisms.

(A) In tumors harboring an EGFR mutation that confers resistance to osimertinib (e.g., C797S), EGFR remains as the primary oncogenic driver and signals through SHP2. SHP2 inhibition by an allosteric SHP2 inhibitor such as IACS-13909 is effective in inhibiting proliferation of the tumor. (B) In tumors where inhibition of EGFR results in compensatory activation of one or more RTKs (“RTK-bypass”), a SHP2 inhibitor can inhibit tumor cell proliferation by blocking signaling downstream of the activated RTKs.